Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors

ABSTRACT

Provided herein are pharmaceutically acceptable salts of 3,5-diaminopyrazoles, for example, pharmaceutically acceptable salts of compounds of Formula IA, that are useful for modulating regulated-in-COPD kinase activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RC kinase-mediated disorder, disease, or condition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/489,231, filed Sep. 17, 2014, which claims the benefit of priority toU.S. Provisional Patent Application Ser. No. 61/879,585, filed Sep. 18,2013, the disclosure of each of which is incorporated by referenceherein in its entirety.

FIELD

Provided herein are pharmaceutically acceptable salts of3,5-diaminopyrazole compounds that are useful for modulatingregulated-in-COPD kinase (RC kinase) activity, and pharmaceuticalcompositions thereof. Also provided herein are methods of their use fortreating, preventing, or ameliorating one or more symptoms of a RCkinase-mediated disorder, disease, or condition BACKGROUND

Regulated-in-COPD kinase (RC kinase) is closely related to MAPKKK3,which directly regulates the pathways of stress-activated protein kinase(SAPK) and extracellular signal-regulated protein kinase (ERK) byactivating SEK and MEK1/2, respectively. See, U.S. Pat. No. 7,829,685,the disclosure of which is incorporated herein by reference in itsentirety. RC kinase is an upstream activator in MAP kinase signalingcascades, capable of phosphorylating MAP kinase kinases such as MKK4 andMKK6. The activation of MKK4 leads to the phosphorylation of JNK-typeMAP kinases, leading to the phosphorylation of c-Jun and thus theactivation of the AP-1 transcription factor complex. As a result,interleukin-8 production is increased, leading to the recruitment ofinflammatory cells, such as neutrophils. The activation of MKK6 leads tothe phosphorylation of p38-type MAP kinases, which is important in theactivation of the immune response and key regulators of inflammatorycytokine expression. The occurrence of cellular stresses, the activationof the transcription factor, and the overproduction of interleukin-8 arecharacteristic of numerous inflammatory diseases. Thus, the regulationof RC kinase activity can potentially be beneficial to patients withinflammatory diseases.

RC kinase has been shown to be highly expressed in the lung and trachea.Some of the expressed sequence tags of human RC kinase are alsoexpressed in the lung epithelial cells and in primary lung cysticfibrosis epithelial cells. Microarray analyses of patients with chronicobstructive pulmonary disease (COPD) show that RC kinase is upregulatedin the lungs of COPD patients. On cellular level, it has been shown thatthe expression of RC kinase is upregulated in response to a hyperosmoticor oxidative stress. For example, the expression of RC kinase in cellsincrease significantly after exposure to potassium chloride or hydrogenperoxide. Potassium chloride subjects cells to a hyperosmotic stress.Hydrogen peroxide subjects cells to an oxidative stress, which impairsthe capacity of B cells to stimulate specific T cells. Such upregulationof RC kinase in cells in response to hyperosmotic and oxidative stresssuggests that higher expression of RC kinase in lungs of COPD patientsmay be the result of cellular stresses caused by the irritants intobacco smoke or stresses caused by inflammatory response to thoseirritants.

Therefore, RC kinase inhibitors are potentially useful for the treatmentof inflammatory diseases, including COPD.

SUMMARY OF THE DISCLOSURE

Provided herein is a pharmaceutically acceptable salt of a3,5-diaminopyrazole of Formula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), or —S(O)₂R^(1a);

R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a),—S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁴ is cyano, aminocarbonyl, —C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b);wherein:

-   -   R^(4a) is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; and    -   R^(4b) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:

-   -   R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or        heterocyclyl;    -   R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,        heteroaryl, or heterocyclyl; and    -   R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl is optionally substituted with one or more substituents Q,where each Q is independently selected from (a) oxo, cyano, halo, nitro,and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —B(R^(a))OR^(d),—B(OR^(a))OR^(d), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d),—P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(e), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a); or (iii) R^(b) and R^(c)together with the N atom to which they are attached form heterocyclyl,optionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl;and (c) —B(R^(e))OR^(g), —B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h),—P(O)(OR^(e))R^(h), —P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —SF₅, —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆alkyl; or (iii) R^(f) and R^(g) together with the N atom to which theyare attached form heterocyclyl.

Also provided herein is a pharmaceutical composition comprising apharmaceutically acceptable salt provided herein, e.g., apharmaceutically acceptable salt of a compound of Formula IA, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable solvate orhydrate thereof; in combination with one or more pharmaceuticallyacceptable carriers.

Further provided herein is a method of treating, preventing, orameliorating one or more symptoms of a RC kinase-mediated disorder,disease, or condition in a subject, comprising administering to thesubject a therapeutically effective amount of a compound disclosedherein, e.g., a compound of Formula IA, including a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Additionally provided herein is a method of modulating RC kinaseactivity, comprising contacting a RC kinase with a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula IA, including a stereoisomer, enantiomer, mixture ofenantiomers, mixture of diastereomers, or isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, e.g., a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a condition, disorder, or disease, or one ormore of the symptoms associated with the condition, disorder, ordisease; or alleviating or eradicating the cause(s) of the condition,disorder, or disease itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a condition,disorder, or disease, and/or its attendant symptoms; barring a subjectfrom acquiring a condition, disorder, or disease; or reducing asubject's risk of acquiring a condition, disorder, or disease.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the condition, disorder, or disease being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “IC₅₀” or “EC₅₀” refers an amount, concentration, or dosage ofa compound that is required for 50% inhibition of a maximal response inan assay that measures such response.

The term “CC₅₀” refers an amount, concentration, or dosage of a compoundthat results in 50% reduction of the viability of a host. In certainembodiments, the CC₅₀ of a compound is the amount, concentration, ordosage of the compound that is required to reduce the viability of cellstreated with the compound by 50%, in comparison with cells untreatedwith the compound.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; Handbook of PharmaceuticalAdditives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company:2007; and Pharmaceutical Preformulation and Formulation, 2nd Edition,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl may optionally be substitutedwith one or more substituents Q as described herein. In certainembodiments, the alkyl is a linear saturated monovalent hydrocarbonradical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1to 6 (C₁₋₆) carbon atoms, or branched saturated monovalent hydrocarbonradical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6(C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkylgroups are also referred as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl (including allisomeric forms), n-propyl, isopropyl, butyl (including all isomericforms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including allisomeric forms), and hexyl (including all isomeric forms). For example,C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbon radicalof 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbonradical of 3 to 6 carbon atoms.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon double bond(s). The alkenyl maybe optionally substituted with one or more substituents Q as describedherein. The term “alkenyl” also embraces radicals having “cis” and“trans” configurations, or alternatively, “Z” and “E” configurations, asappreciated by those of ordinary skill in the art. As used herein, theterm “alkenyl” encompasses both linear and branched alkenyl, unlessotherwise specified. For example, C₂₋₆ alkenyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon triple bond(s). The alkynyl maybe optionally substituted with one or more substituents Q as describedherein. The term “alkynyl” also encompasses both linear and branchedalkynyl, unless otherwise specified. In certain embodiments, the alkynylis a linear monovalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15(C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH) and propargyl(—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which may be optionally substituted with one or more substituents Q asdescribed herein. In one embodiment, cycloalkyl groups may be saturated,and/or bridged, and/or non-bridged, and/or fused bicyclic groups. Incertain embodiments, the cycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent multicyclic aromatic group that contain at least one aromaticcarbon ring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀),from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, andterphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, whereone of the rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthyl,indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certainembodiments, aryl may be optionally substituted with one or moresubstituents Q as described herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups, wherein the aralkyl orarylalkyl is optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, the aralkyl has from 7 to 30(C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16 (C₇₋₁₆) carbon atoms.Examples of aralkyl groups include, but are not limited to, benzyl,2-phenylethyl, and 3-phenylpropyl.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupand/or multicyclic aromatic group that contain at least one aromaticring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, and N in the ring.Heteroaryl groups are bonded to the rest of the molecule through thearomatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, and/or one to four N atoms, provided that thetotal number of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments,heteroaryl may also be optionally substituted with one or moresubstituents Q as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system and/or multicyclic ring system thatcontains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, or N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of the moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay include a fused or bridged ring system, and in which the nitrogen orsulfur atoms may be optionally oxidized, the nitrogen atoms may beoptionally quaternized, and some rings may be partially or fullysaturated, or aromatic. The heterocyclyl may be attached to the mainstructure at any heteroatom or carbon atom which results in the creationof a stable compound. Examples of such heterocyclic radicals include,but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl,benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, (3-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted with one or more substituents Q as describedherein.

The term “heterocyclylalkyl” refers to a monovalent alkyl groupsubstituted with one or more heterocyclyl groups, wherein the alkyl andheterocyclyl are each as defined herein. In certain embodiments, theheteroaralkyl is optionally substituted with one or more substituents Qas described herein.

The term “alkoxy” refers to —O-alkyl, wherein the alkyl is as definedherein. For example, the term “C₁₋₆ alkoxy” refers to —O—C₁₋₆ alkyl.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heteroaryl, or heterocyclyl group, may be substituted with oneor more substituents Q, each of which is independently selected from,e.g., (a) oxo (═O), halo, cyano (—CN), nitro (—NO₂), andpentafluorosulfanyl (—SF₅); (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclylalkyl, each of which is further optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(e), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclylalkyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheteroaryl or heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q^(a). As usedherein, all groups that can be substituted are “optionally substituted,”unless otherwise specified.

In one embodiment, each Q^(a) is independently selected from the groupconsisting of (a) oxo, cyano, halo, nitro, and pentafluorosulfanyl(—SF₅); and (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclylalkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —R^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; or (ii)R^(f) and R^(g) together with the N atom to which they are attached formheteroaryl or heterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules of a compound, which has anenantiomeric excess of no less than about 50%, no less than about 70%,no less than about 80%, no less than about 90%, no less than about 91%,no less than about 92%, no less than about 93%, no less than about 94%,no less than about 95%, no less than about 96%, no less than about 97%,no less than about 98%, no less than about 99%, no less than about99.5%, or no less than about 99.8%. In certain embodiments, the compoundcomprises about 95% or more of one enantiomer and about 5% or less ofthe other enantiomer based on the total weight of the racemate inquestion.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the compound about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “pharmaceutically acceptable salt” refers to salts of aceticacid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid,alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid,glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid,undecylenic acid, and valeric acid.

In one embodiment, the compound provided herein is an acetic acid salt.In one embodiment, the compound provided herein is a camphorsulfonicacid salt. In one embodiment, the compound provided herein is a citricacid salt. In one embodiment, the compound provided herein is anethanesulfonic acid salt. In one embodiment, the compound providedherein is a formic acid salt. In one embodiment, the compound providedherein is a hydrobromic acid salt. In one embodiment, the compoundprovided herein is a hydrochloric acid salt. In one embodiment, thecompound provided herein is a methanesulfonic acid salt. In oneembodiment, the compound provided herein is an oxalic acid salt. In oneembodiment, the compound provided herein is a phosphoric acid salt. Inone embodiment, the compound provided herein is a sulfuric acid salt. Inone embodiment, the compound provided herein is a tartaric acid salt. Inone embodiment, the compound provided herein is a p-toluenesulfonic acidsalt. In one embodiment, the compound provided herein is atrifluoroacetic acid salt.

The pharmaceutically acceptable salts provided herein includes salts ofany stoichiometry. For example, in some embodiments, the molar ratio offree base compound to acid is 1:1. In some embodiments, the molar ratioof free base compound to acid is 1:2. In some embodiments, the molarratio of free base compound to acid is 1:3. In some embodiments, themolar ratio of free base compound to acid is 2:3. In some embodiments,the molar ratio of free base compound to acid is 1:3. In someembodiments, the molar ratio of free base compound to acid is 2:1. Insome embodiments, the molar ratio of free base compound to acid is 3:1.In some embodiments, the molar ratio of free base compound to acid is3:2.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17(¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125(¹²⁵I), iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). Incertain embodiments, an “isotopic variant” of a compound is in a stableform, that is, non-radioactive. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, for example, or any carboncan be ¹³C, for example, or any nitrogen can be ¹⁵N, for example, or anyoxygen can be ¹⁸O, for example, where feasible according to the judgmentof one of skill. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of deuterium (D).

The term “solvate” refers to a salt provided herein, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “RC kinase” refers to regulated in COPD kinase or a variantthereof. RC kinase variants include proteins substantially homologous toa native RC kinase, i.e., proteins having one or more naturally ornon-naturally occurring amino acid deletions, insertions, orsubstitutions (e.g., RC kinase derivatives, homologs and fragments), ascompared to the amino acid sequence of a native RC kinase. The aminoacid sequence of a RC kinase variant is at least about 80% identical, atleast about 90% identical, or at least about 95% identical to a nativeRC kinase. Some examples of RC kinases are disclosed in U.S. Pat. No.7,829,685, the disclosure of which is incorporated herein by referencein its entirety.

The terms “RC kinase-mediated disorder, disease, or condition” and “adisorder, disease, or condition mediated by RC kinase” refer to adisorder, disease, or condition, characterized by abnormal ordysregulated, e.g., less than or greater than normal, RC kinaseactivity. Abnormal RC kinase functional activity might arise as theresult of RC kinase overexpression in cells, expression of RC kinase incells which normally do not express RC kinase, or dysregulation due toconstitutive activation, caused, for example, by a mutation in RCkinase. A RC kinase-mediated disorder, disease, or condition may becompletely or partially mediated by abnormal or dysregulated RC kinaseactivity. In particular, a RC kinase-mediated disorder, disease, orcondition is one in which modulation of a RC kinase activity results insome effect on the underlying disorder, disease, or condition, e.g., aRC kinase inhibitor results in some improvement in at least some ofpatients being treated.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, oran isotopic variant thereof; or a pharmaceutically solvate or hydratethereof” has the same meaning as the phrase “an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant of the compoundor salt referenced therein; or a pharmaceutically solvate or hydrate ofthe compound or salt referenced therein; or a pharmaceutically solvateor hydrate of an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, a tautomer, a mixture of two or more tautomers,or an isotopic variant of the compound or salt referenced therein.”

Compounds

In one embodiment, provided herein is a pharmaceutically acceptabalesalt of a 3,5-diaminopyrazole of Formula IA:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically solvate or hydratethereof; wherein:

R¹ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), or —S(O)₂R^(1a);

R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a),—S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁴ is cyano, aminocarbonyl, —C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b);wherein:

-   -   R^(4a) is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; and    -   R^(4b) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:

-   -   R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or        heterocyclyl; and    -   R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,        heteroaryl, or heterocyclyl; and    -   R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl is optionally substituted with one or more substituents Q,where each Q is independently selected from (a) oxo, cyano, halo, nitro,and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —B(R^(a))OR^(d),—B(OR^(a))OR^(d), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(1a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d),—P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(e), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a); or (iii) R^(b) and R^(c)together with the N atom to which they are attached form heterocyclyl,optionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl;and (c) —B(R^(e))OR^(g), —B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h),—P(O)(OR^(e))R^(h), —P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —SF₅, —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆alkyl; or (iii) R^(f) and R^(g) together with the N atom to which theyare attached form heterocyclyl.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a 3,5-diaminopyrazole of Formula I:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein:

R¹ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(a), or —S(O)₂R^(1a);

R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR¹R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a),—S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁴ is cyano, aminocarbonyl, —C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b);wherein:

-   -   R^(4a) is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; and    -   R^(4b) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:

-   -   R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or        heterocyclyl; and    -   R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,        heteroaryl, or heterocyclyl; and    -   R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl is optionally substituted with one or more substituents Q,where each Q is independently selected from (a) oxo, cyano, halo, nitro,and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —B(R^(a))OR^(d),—B(OR^(a))OR^(d), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(1a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d),—P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(e), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a); or (iii) R^(b) and R^(c)together with the N atom to which they are attached form heterocyclyl,optionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl;and (c) —B(R^(e))OR^(g), —B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h),—P(O)(OR^(e))R^(h), —P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —SF₅, —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆alkyl; or (iii) R^(f) and R^(g) together with the N atom to which theyare attached form heterocyclyl.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula IA or I, or a stereoisomer, enantiomer, mixtureof enantiomers, mixture of diastereomers, or isotopic variant thereof;or a pharmaceutically acceptable solvate, hydrate, or prodrug thereof,wherein:

R¹ and R³ are hydrogen;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy areeach optionally substituted with one or more substituents Q^(a);

R⁴ is cyano, aminocarbonyl, —C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b);

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d);

R^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is further optionallysubstituted with one or more substituents Q^(a); and (c)—B(R^(1a))OR^(1d), —C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c),and —S(O)₂R^(1a); and

R^(1a), R^(1b), R^(1c), R^(1d), R^(4a), R^(4b), R^(5c), R^(5d), R^(e),and Q^(a) are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula IA or I, or a stereoisomer, enantiomer,mixture of enantiomers, mixture of diastereomers, or isotopic variantthereof; or a pharmaceutically acceptable solvate, hydrate, or prodrugthereof, wherein:

R¹ and R³ are hydrogen;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, and methoxy;

R⁴ is cyano, aminocarbonyl, —C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b);

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d);

R^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q, wherein eachsubstituent Q is independently selected from fluoro, chloro, bromo,cyano, nitro, pentafluorosulfanyl, methyl, trifluoromethyl,hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl, chlorophenyl,thienyl, triazolyl, pyridinyl, benzimidazolyl, methylpiperazinyl,tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy, difluoromethoxy,trifluoromethoxy, fluorobenzyloxy, chlorothiazolylmethoxy,pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl; and

R^(4a), R^(4b), R^(5c), R^(5d), and R^(5e) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ;

R⁴ is cyano, aminocarbonyl, or —C(O)N═CHR^(4a)

R⁵ is —NHCH₂R^(5a);

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents Q; and

R^(4a) and Q are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy areeach optionally substituted with one or more substituents Q^(a);

R⁴ is cyano, aminocarbonyl, or —C(O)N═CHR^(4a)

R⁵ is —NHCH₂R^(5a);

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is optionally substitutedwith one or more substituents Q^(a); and (c) —B(R^(1a))OR^(1d),—C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a);and

R^(1a), R^(1b), R^(1c), R^(1d), R^(4a), and Q^(a) are each as definedherein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, and methoxy;

R⁴ is cyano, aminocarbonyl, or —C(O)N═CH(methoxyphenyl);

R⁵ is —NHCH₂R^(5a); and

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from fluoro,chloro, bromo, cyano, nitro, pentafluorosulfanyl, methyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, thienyl, triazolyl, pyridinyl, benzimidazolyl,methylpiperazinyl, tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy,difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl.

In still another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,3,4,5-tetrachlorophenyl, 4-cyanophenyl, 4-nitrophenyl,4-t-butylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, or pyridin-3-yl;

R⁴ is cyano, aminocarbonyl, or —C(O)N═CH(4-methoxyphenyl);

R⁵ is —NHCH₂R^(5a); and

R^(5a) is (i) phenyl or naphth-1-yl; (ii) 4-chlorophenyl, 4-cyanophenyl,4-nitrophenyl, 4-pentafluorosulfanylphenyl, 4-trifluoromethylphenyl,2-thien-2-ylphenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-pyridin-2-ylphenyl, 4-(benzimidazol-1-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-(2-hydroxyethoxy)phenyl, 4-(2-hydroxyethoxy)phenyl,4-(4-fluorobenzyloxy)phenyl, 3-(pyrimidin-2-yloxy)phenyl,2-hydroxyphenyl, 4-hydroxyphenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(4-trifluoromethylpyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl,2-(hydroxycarbonylmethoxy)phenyl, or 4-methylsulfonylphenyl; (iii)2-fluoro-6-chlorophenyl, 4-fluoro-3-cyanophenyl,4-fluoro-2-methylphenyl, 4-fluoro-2-hydroxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-methoxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-trifluoromethoxy-phenyl,2,4-dichlorophenyl, 2-chloro-6-hydroxyphenyl, 4-chloro-2-hydroxyphenyl,5-chloro-2-hydroxyphenyl, 5-bromo-2-hydroxyphenyl,2-nitro-5-hydroxyphenyl, 3-nitro-4-hydroxyphenyl,4-nitro-3-hydroxyphenyl, 5-nitro-2-hydroxyphenyl,3-nitro-4-methoxyphenyl, 5-trifluoromethyl-2-methoxyphenyl,2-hydroxy-4-methylphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl,2-hydroxy-6-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-difluoromethoxyphenyl,3-methoxy-4-(2-chlorothiazol-5-ylmethoxy)phenyl, or5-(hydroxyboryl)-2-methoxyphenyl; (iv) 3,5-difluoro-4-hydroxyphenyl,2,4-dichloro-6-hydroxyphenyl, 2,3-dimethyl-4-methoxyphenyl,4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-2,6-dimethylphenyl,4-hydroxy-3,5-dimethylphenyl, 2,4,6-trihydroxyphenyl,3-hydroxy-4,5-dimethoxyphenyl, or4-hydroxy-5-methoxy-3-dimethylaminophenyl; (v)5-(4-chlorophenyl)furan-2-yl, 5-(hydroxymethyl)furan-2-yl, pyrrol-2-yl,pyrrol-3-yl, 1-phenylsulfonylpyrrol-2-yl, thien-2-yl,2-(pyridin-2-yl)thien-5-yl, 3-(4-fluorophenyl)pyrazol-4-yl,3-chloro-5-trifluoromethylpyrazol-4-yl,1-methyl-3-phenylthiomethyl-5-chloropyrazol-4-yl,1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl,3-(4-fluorophenyl)pyrazol-4-yl, imidazol-4-yl,2-ethyl-5-methylimidazol-4-yl, 2-phenyl-5-chloroimidazol-4-yl,5-methylisoxazol-5-yl, 2-chloro-thiazol-5-yl, 2-aminothiazol-5-yl,4-methylthiazol-5-yl, 2-tetrahydropyrrol-1-ylpyridin-3-yl,3-tetrahydropyrrol-1-ylpyridin-5-yl, 2-(morpholin-4-yl)pyridin-5-yl,2-chloropyridin-3-yl, 2-chloropyridin-5-yl, 2-chloropyridin-6-yl,3-fluoropyridin-2-yl, 2-methoxypyridin-5-yl, pyrazin-2-yl,3,5-dichloropyrazin-2-yl, benzo[d][1,2,3]thiadiazol-5-yl,2-methylindol-3-yl, 1-methyl-2-chloroindol-3-yl,4,5,6,7-tetrafluoroindol-3-yl, 6-fluoro-4H-benzo[d][1,3]dioxin-8-yl, orbenzimidazol-2-yl; or (vi) 1-(benzyloxycarbonyl)tetrahydropyrrol-2-yl,piperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or4-acetylpiperazin-1-yl.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula IA or I, or a stereoisomer, enantiomer, mixtureof enantiomers, mixture of diastereomers, or isotopic variant thereof;or a pharmaceutically acceptable solvate, hydrate, or prodrug thereof,wherein:

R¹ and R³ are hydrogen;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy areeach optionally substituted with one or more substituents Q^(a);

R⁴ is aminocarbonyl;

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d);

R^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is further optionallysubstituted with one or more substituents Q^(a); and (c)—B(R^(1a))OR^(1d), —C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c),and —S(O)₂R^(1a); and

R^(1a), R^(1b), R^(1c), R^(1d), R^(4a), R^(4b), R^(5c), R^(5d), R^(5e),and Q^(a) are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula IA or I, or a stereoisomer, enantiomer,mixture of enantiomers, mixture of diastereomers, or isotopic variantthereof; or a pharmaceutically acceptable solvate, hydrate, or prodrugthereof, wherein:

R¹ and R³ are hydrogen;

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, and methoxy;

R⁴ is aminocarbonyl;

R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d);

R^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q, wherein eachsubstituent Q is independently selected from fluoro, chloro, bromo,cyano, nitro, pentafluorosulfanyl, methyl, trifluoromethyl,hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl, chlorophenyl,thienyl, triazolyl, pyridinyl, benzimidazolyl, methylpiperazinyl,tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy, difluoromethoxy,trifluoromethoxy, fluorobenzyloxy, chlorothiazolylmethoxy,pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl; and

R^(4a), R^(4b), R^(5c), R^(5d), and R^(5e) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ;

R⁴ is aminocarbonyl;

R⁵ is —NHCH₂R^(5a);

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents Q; and

R^(4a) and Q are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy areeach optionally substituted with one or more substituents Q^(a);

R⁴ is aminocarbonyl;

R⁵ is —NHCH₂R^(5a);

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is optionally substitutedwith one or more substituents Q^(a); and (c) —B(R^(1a))OR^(1d),—C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a);and

R^(1a), R^(1b), R^(1c), R^(1d), R^(4a), and Q^(a) are each as definedherein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, and methoxy;

R⁴ is aminocarbonyl;

R⁵ is —NHCH₂R^(5a); and

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from fluoro,chloro, bromo, cyano, nitro, pentafluorosulfanyl, methyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, thienyl, triazolyl, pyridinyl, benzimidazolyl,methylpiperazinyl, tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy,difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl.

In still another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IA or I, or a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable solvate,hydrate, or prodrug thereof; wherein:

R¹ and R³ are hydrogen;

R² is cyclopropyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,3,4,5-tetrachlorophenyl, 4-cyanophenyl, 4-nitrophenyl,4-t-butylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, or pyridin-3-yl;

R⁴ is aminocarbonyl;

R⁵ is —NHCH₂R^(5a); and

R^(5a) is (i) phenyl or naphth-1-yl; (ii) 4-chlorophenyl, 4-cyanophenyl,4-nitrophenyl, 4-pentafluorosulfanylphenyl, 4-trifluoromethylphenyl,2-thien-2-ylphenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-pyridin-2-ylphenyl, 4-(benzimidazol-1-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-(2-hydroxyethoxy)phenyl, 4-(2-hydroxyethoxy)phenyl,4-(4-fluorobenzyloxy)phenyl, 3-(pyrimidin-2-yloxy)phenyl,2-hydroxyphenyl, 4-hydroxyphenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(4-trifluoromethylpyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl,2-(hydroxycarbonylmethoxy)phenyl, or 4-methylsulfonylphenyl; (iii)2-fluoro-6-chlorophenyl, 4-fluoro-3-cyanophenyl,4-fluoro-2-methylphenyl, 4-fluoro-2-hydroxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-methoxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-trifluoromethoxy-phenyl,2,4-dichlorophenyl, 2-chloro-6-hydroxyphenyl, 4-chloro-2-hydroxyphenyl,5-chloro-2-hydroxyphenyl, 5-bromo-2-hydroxyphenyl,2-nitro-5-hydroxyphenyl, 3-nitro-4-hydroxyphenyl,4-nitro-3-hydroxyphenyl, 5-nitro-2-hydroxyphenyl,3-nitro-4-methoxyphenyl, 5-trifluoromethyl-2-methoxyphenyl,2-hydroxy-4-methylphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl,2-hydroxy-6-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-difluoromethoxyphenyl,3-methoxy-4-(2-chlorothiazol-5-ylmethoxy)phenyl, or5-(hydroxyboryl)-2-methoxyphenyl; (iv) 3,5-difluoro-4-hydroxyphenyl,2,4-dichloro-6-hydroxyphenyl, 2,3-dimethyl-4-methoxyphenyl,4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-2,6-dimethylphenyl,4-hydroxy-3,5-dimethylphenyl, 2,4,6-trihydroxyphenyl,3-hydroxy-4,5-dimethoxyphenyl, or4-hydroxy-5-methoxy-3-dimethylaminophenyl; (v)5-(4-chlorophenyl)furan-2-yl, 5-(hydroxymethyl)furan-2-yl, pyrrol-2-yl,pyrrol-3-yl, 1-phenylsulfonylpyrrol-2-yl, thien-2-yl,2-(pyridin-2-yl)thien-5-yl, 3-(4-fluorophenyl)pyrazol-4-yl,3-chloro-5-trifluoromethylpyrazol-4-yl,1-methyl-3-phenylthiomethyl-5-chloropyrazol-4-yl,1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl,3-(4-fluorophenyl)pyrazol-4-yl, imidazol-4-yl,2-ethyl-5-methylimidazol-4-yl, 2-phenyl-5-chloroimidazol-4-yl,5-methylisoxazol-5-yl, 2-chloro-thiazol-5-yl, 2-aminothiazol-5-yl,4-methylthiazol-5-yl, 2-tetrahydropyrrol-1-ylpyridin-3-yl,3-tetrahydropyrrol-1-ylpyridin-5-yl, 2-(morpholin-4-yl)pyridin-5-yl,2-chloropyridin-3-yl, 2-chloropyridin-5-yl, 2-chloropyridin-6-yl,3-fluoropyridin-2-yl, 2-methoxypyridin-5-yl, pyrazin-2-yl,3,5-dichloropyrazin-2-yl, benzo[d][1,2,3]thiadiazol-5-yl,2-methylindol-3-yl, 1-methyl-2-chloroindol-3-yl,4,5,6,7-tetrafluoroindol-3-yl, 6-fluoro-4H-benzo[d][1,3]dioxin-8-yl, orbenzimidazol-2-yl; or (vi) 1-(benzyloxycarbonyl)tetrahydropyrrol-2-yl,piperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or4-acetylpiperazin-1-yl.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula I-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R³, R⁴, andR⁵ are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula I-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R⁴, andR⁵ are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula I-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R⁴, and R⁵are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula II:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, andR⁵ are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula II-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R³, and R⁵are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula II-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², and R⁵are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula II-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R² and R⁵ areeach as defined herein.

In yet another embodiment, provided herein is a salt of a compound ofFormula III:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, andR⁵ are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula III-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R³, and R⁵are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula III-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², and R⁵are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula III-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R² and R⁵ areeach as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IV:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein:

each R⁶ is independently (a) cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q or Q^(a); or (c) —B(R^(1a))OR^(1d), —B(OR^(1a))OR^(1d),—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

n is an integer of 0, 1, 2, 3, 4, or 5; and

R¹, R³, R⁴, R⁵, R^(1a), R^(1b), R^(1c), R^(1d), Q, and Q^(a) are each asdefined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula IV-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R³, R⁴, R⁵, R⁶,and n are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula IV-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R⁴, R⁵, R⁶,and n are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula IV-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R⁴, R⁵, R⁶, andn are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula V:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R³, R⁵, R⁶,and n are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula V-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R³, R⁵, R⁶, andn are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula V-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R⁵, R⁶, andn are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula V-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable, solvate, hydrate, or prodrug thereof; wherein R⁵, R⁶, and nare each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula VI:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R³, R⁵, R⁶,and n are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula VI-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R³, R⁵, R⁶, andn are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula V-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R⁵, R⁶, andn are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula V-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R⁵, R⁶, and nare each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XIII:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴,R^(5a), R^(5c), and R^(5d) are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula XIII-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R³, R⁴,R^(5a), R^(5c), and R^(5d) are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula XIII-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R⁴,R^(5a), R^(5c), and R^(5d) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XIII-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R⁴, R^(5a),R^(5c), and R^(5d) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XIV:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R³,R^(5a), R^(5c), and R^(5d) are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula XIV-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R³, R^(5a),R^(5c), and R^(5d) are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula XIV-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R^(5a),R^(5c), and R^(5d) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XIV-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R^(5a),R^(5c), and R^(5d) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XV:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R², R³,R^(5a), R^(5c), and R^(5d) are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula XVI-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R³, R^(5a),R^(5c), and R^(5d) are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula XIV-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R² R^(5a),R^(5c), and R^(5d) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XIV-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R², R^(5a),R^(5c), and R^(5d) are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XV:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R³, R⁴,R^(5a), R^(5c), R^(5d), R⁶, and n are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula XV-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R³, R⁴, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula XV-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R⁴, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XV-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R⁴, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XVI:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R³, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula XVI-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R³, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula XVI-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XVI-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R^(5a), R^(5c),R^(5d), R⁶, and n are each as defined herein.

In still another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XVII:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R³, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula XVII-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R³, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In another embodiment, provided herein is a pharmaceutically acceptablesalt of a compound of Formula XVII-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R¹, R^(5a),R^(5c), R^(5d), R⁶, and n are each as defined herein.

In yet another embodiment, provided herein is a pharmaceuticallyacceptable salt of a compound of Formula XVII-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein R^(5a), R^(5c),R^(5d), R⁶, and n are each as defined herein.

The groups, R¹, R², R³, R⁴, R⁵, R⁶, R^(1a), R^(1b), R^(1c), R^(1d),R^(4a), R^(4b), R^(5a), R^(5c), R^(5d), R^(5e), and n in formulaedescribed herein, including Formulae I to XVII, I-a to XVII-a, I-b toXVII-b, and I-c to XVII-c, are further defined herein. All combinationsof the embodiments provided herein for such groups are within the scopeof this disclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R¹ is C₂₋₆ alkenyl, optionally substituted with oneor more substituents Q. In certain embodiments, R¹ is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is C₃₋₁₀ cycloalkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹ is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹ is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R² is C₃₋₁₀ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R² iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R² is cyclopropyl or cyclohexyl, each optionallysubstituted with one or more substituents Q.

In certain embodiments, R² is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R² is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q, wherein each Qindependently selected from cyano, nitro, halo, C₁₋₆ alkyl, and C₁₋₆alkoxy, where the alkyl and alkoxy are each optionally substituted withone or more substituents Q^(a). In certain embodiments, R² is C₆₋₁₄aryl, optionally substituted with one or more substituents Q, whereineach substituent Q is independently selected from cyano, nitro, chloro,methyl, butyl, and methoxy.

In certain embodiments, R² is monocyclic C₆₋₁₄ aryl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is monocyclic C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q, wherein each substituent Q is independently selectedfrom cyano, nitro, halo, heteroaryl, heterocyclyl, C₁₋₆ alkyl, and C₁₋₆alkoxy, where the alkyl and alkoxy are each optionally substituted withone or more substituents Q^(a). In certain embodiments, R² is monocyclicC₆₋₁₄ aryl, optionally substituted with one or more substituents Q,wherein each substituent Q is independently selected from cyano, nitro,chloro, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl,methyl, butyl, and methoxy.

In certain embodiments, R² is phenyl, optionally substituted with one ormore substituents Q. In certain embodiments, R² is phenyl, optionallysubstituted with one, two, three, four, or five substituents Q. Incertain embodiments, R² is phenyl, optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from cyano, nitro, halo, heteroaryl,heterocyclyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxyare each optionally substituted with one or more substituents Q^(a). Incertain embodiments, R² is phenyl, optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from cyano, nitro, chloro, 5- or 6-memberedheteroaryl, 5- or 6-membered heterocyclyl methyl, butyl, and methoxy. Incertain embodiments, R² is phenyl, optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from cyano, nitro, chloro, methyl, t-butyl, andmethoxy. In certain embodiments, R² is phenyl, cyanophenyl, nitrophenyl,chlorophenyl, dichlorophenyl, tetrachlorophenyl, butylphenyl,dimethylphenyl, or methoxyphenyl. In certain embodiments, R² is phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 2,3,4,5-tetrachlorophenyl, 4-cyanophenyl,4-nitrophenyl, 4-t-butylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl,4-(4-methylpiperazin-1-yl)phenyl, 4-(morpholinomethyl)phenyl,4-morpholinophenyl, 4-(pyridin-2-yl)phenyl,4-(4-isopropylpiperazin-1-yl)phenyl, or 4-(1H-imidazol-1-yl)phenyl.

In certain embodiments, R² is heteroaryl, optionally substituted withone or more substituents Q. In certain embodiments, R² is bicyclicheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is 1H-indazol-5-yl. In certain embodiments, R²is monocyclic heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is 5- or 6-memberedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is 5-membered heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R² is6-membered heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is pyridinyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is pyridin-3-yl, optionally substituted with one or more substituents Q.In certain embodiments, R² is pyridin-3-yl. In certain embodiments, R²is 6-morpholinopyridin-3-yl.

In certain embodiments, R² is heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R² is monocyclicheterocyclyl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is 5- or 6-membered heterocyclyl, optionallysubstituted with one or more substituents Q.

In certain embodiments, R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q, wherein each substituent Q is independentlyselected from cyano, nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, whereinthe alkyl and alkoxy are each optionally substituted with one or moresubstituents Q^(a). In certain embodiments, R² is C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q, wherein each substituent Qis independently selected from cyano, nitro, chloro, methyl, butyl, andmethoxy.

In certain embodiments, R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, orheteroaryl, each of which is optionally substituted with one, two,three, four, or five substituents Q. In certain embodiments, R² is C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which is optionallysubstituted with one, two, three, four, or five substituents Q, whereineach substituent Q is independently selected from cyano, nitro, halo,C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy are eachoptionally substituted with one or more substituents Q^(a). In certainembodiments, R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each ofwhich is optionally substituted with one, two, three, four, or fivesubstituents Q, wherein each substituent Q is independently selectedfrom cyano, nitro, chloro, methyl, butyl, and methoxy.

In certain embodiments, R² is cyclopropyl, cyclohexyl, phenyl, orpyridinyl, each of which is optionally substituted with one, two, three,four, or five substituents Q. In certain embodiments, R² is cyclopropyl,cyclohexyl, phenyl, or pyridinyl, each of which is optionallysubstituted with one, two, three, four, or five substituents Q, whereineach substituent Q is independently selected from cyano, nitro, halo,C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy are eachoptionally substituted with one or more substituents Q^(a). In certainembodiments, R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, eachof which is optionally substituted with one, two, three, four, or fivesubstituents Q, wherein each substituent Q is independently selectedfrom cyano, nitro, chloro, methyl, butyl, and methoxy. In certainembodiments, R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, eachof which is optionally substituted with one, two, three, four, or fivesubstituents Q, wherein each substituent Q is independently selectedfrom cyano, nitro, chloro, methyl, butyl, and methoxy. In certainembodiments, R² is cyclopropyl, cyclohexyl, phenyl, cyanophenyl,nitrophenyl, chlorophenyl, dichlorophenyl, tetrachlorophenyl,butylphenyl, dimethylphenyl, methoxyphenyl, or pyridinyl.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R³ is C₂₋₆ alkenyl, optionally substituted with oneor more substituents Q. In certain embodiments, R³ is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R³ is C₃₋₁₀ cycloalkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R³ is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R³ is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R³ is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R³ is heterocyclyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R³ is —C(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R³ is —C(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R³ is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R³ is —C(NR^(1a))NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R³ is —S(O)R^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R³ is —S(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R³ is —S(O)NR^(1b)R^(1c), wherein R^(1b)and R^(1c) are each as defined herein. In certain embodiments, R³ is—S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R⁴ is cyano. In certain embodiments, R⁴ isaminocarbonyl (—C(O)NH₂). In certain embodiments, R⁴ is—C(O)N═CR^(4a)R^(4b), wherein R^(4a) and R^(4b) is each as definedherein. In certain embodiments, R⁴ is —C(O)N═CHR^(4a), wherein R^(4a) isas defined herein. In certain embodiments, R⁴ is —C(O)N═CHR^(4a),wherein R^(4a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In certain embodiments, R⁴ is —C(O)N═CHR^(4a), whereinR^(4a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one or more substituents Q.In certain embodiments, R⁴ is —C(O)N═CHR^(4a), wherein R^(4a) is C₃₋₁₀cycloalkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R⁴ is —C(O)N═CHR^(4a), wherein R^(4a) is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R⁴ is —C(O)N═CH-phenyl, where the phenyl is optionallysubstituted with one, two, three, four, or five substituents Q. Incertain embodiments, R⁴ is —C(O)N═CH-(methoxyphenyl). In certainembodiments, R⁴ is —C(O)N═CH-(4-methoxyphenyl). In certain embodiments,R⁴ is —C(O)NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are each as definedherein.

In certain embodiments, R^(4a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(4a) is C₂₋₆alkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(4a) is C₂₋₆ alkynyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(4a) is C₃₋₁₀cycloalkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(4a) is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R^(4a) is monocyclicC₆₋₁₄ aryl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(4a) is monocyclic C₆₋₁₄ aryl, optionallysubstituted with one or more C₁₋₆ alkoxy groups. In certain embodiments,R^(4a) is phenyl, optionally substituted with one, two, three, four, orfive substituents Q. In certain embodiments, R^(4a) is phenyl,optionally substituted with one, two, three, four, or five C₁₋₆ alkoxygroups. In certain embodiments, R^(4a) is methoxyphenyl. In certainembodiments, R^(4a) is 4-methoxyphenyl. In certain embodiments, R^(4a)is C₇₋₁₅ aralkyl, optionally substituted with one or more substituentsQ. In certain embodiments, R^(4a) is heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(4a) isheterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R^(4b) is hydrogen. In certain embodiments,R^(4b) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(4b) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(4b) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(4b) is C₃₋₁₀ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(4b) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(4b) is phenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(4b) is methoxyphenyl. In certain embodiments, R^(4b) is4-methoxyphenyl. In certain embodiments, R^(4b) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(4b) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(4b) is heterocyclyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(4b) is —C(O)R^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R^(4b) is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(4b) is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(4b) is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R^(4b) is—S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(4b) is —S(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(4b) is —S(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(4b) is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein.

In certain embodiments, R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d), whereinR^(5a), R^(5c), R^(5d), and R^(5e) are each as defined herein. Incertain embodiments, R⁵ is —NHCR^(5a)R^(5c)R^(5d), wherein R^(5a),R^(5c), and R^(5d) are each as defined herein. In certain embodiments,R⁵ is —NHCH₂R^(5a), wherein R^(5a) is as defined herein. In certainembodiments, R⁵ is —NHCH₂R^(5a), wherein R^(5a) is C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q. In certain embodiments, R⁵is —NHCH₂R^(5a), wherein R^(5a) is C₃₋₁₀ cycloalkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁵is —NHCH₂R^(5a), wherein R^(5a) is C₆₋₁₄ aryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁵ is—NHCH₂R^(5a), wherein R^(5a) is C₇₋₁₅ aralkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁵ is—NHCH₂R^(5a), wherein R^(5a) is heteroaryl, optionally substituted withone or more substituents Q. In certain embodiments, R⁵ is —NHCH₂R^(5a),wherein R^(5a) is heterocyclyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁵ is —NHCH₂R^(5a), whereinR^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q.

In certain embodiments, R^(5a) is C₃₋₁₀ cycloalkyl, optionallysubstituted with one or more substituents Q.

In certain embodiments, R^(5a) is C₆₋₁₄ aryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(5a) is C₆₋₁₄aryl, optionally substituted with one, two, three, four, or fivesubstituents Q, wherein each substituent Q is independently selectedfrom (a) halo, cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl,heteroaryl, and heterocyclyl, each optionally substituted with one ormore substituents Q^(a); and (c) —B(R^(1a))OR^(1d), —OR^(1a),—NR^(1b)R^(1c), and —S(O)₂R^(1a), where R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R^(5a) isC₆₋₁₄ aryl, optionally substituted with one or more substituents Q,wherein each substituent Q is independently selected from fluoro,chloro, bromo, cyano, nitro, pentafluorosulfanyl, methyl,trifluoromethyl, thienyl, triazolyl, pyridinyl, benzimidazolyl,methylpiperazinyl, hydroxyl, methoxy, difluoromethoxy, trifluoromethoxy,fluorobenzyloxy, chlorothiazolylmethoxy, pyrimidinyloxy,trifluoromethylpyrimidinyloxy, trifluoromethylpyridinyloxy,hydroxyethoxy, hydroxycarbonylmethoxy, dimethylamino, hydroxyboryl, andmethylsulfonyl.

In certain embodiments, R^(5a) is phenyl or naphthyl, each optionallysubstituted with one or more substituents Q. In certain embodiments,R^(5a) is phenyl or naphthyl, each optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from (a) halo, cyano, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, heteroaryl, and heterocyclyl, eachoptionally substituted with one or more substituents Q^(a); and (c)—B(R^(1a))OR^(d), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a), whereR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5a) is phenyl or naphthyl, each optionallysubstituted with one, two, three, four, or five substituents Q, whereineach substituent Q is independently selected from fluoro, chloro, bromo,cyano, nitro, pentafluorosulfanyl, methyl, trifluoromethyl, thienyl,triazolyl, pyridinyl, benzimidazolyl, methylpiperazinyl, hydroxyl,methoxy, difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,dimethylamino, hydroxyboryl, and methylsulfonyl.

In certain embodiments, R^(5a) is (i) unsubstituted C₆₋₁₄ aryl: phenylor naphthyl; (ii) monosubstituted C₆₋₁₄ aryl: chlorophenyl, cyanophenyl,nitrophenyl, pentafluorosulfanylphenyl, trifluoromethylphenyl,hydroxyphenyl, methoxyphenyl, (fluorobenzyloxy)phenyl,(hydroxyethoxy)phenyl, (hydroxycarbonylmethoxy)phenyl,(pyrimidinyloxy)phenyl, (trifluoromethylpyrimidinyloxy)phenyl,(trifluoromethylpyridinyloxy)phenyl, thienylphenyl, triazolylphenyl,pyridinylphenyl, benzimidazolylphenyl, methylpiperazinylphenyl, ormethylsulfonylphenyl; (iii) disubstituted C₆₋₁₄ aryl: dichlorophenyl,fluoro-chloro-phenyl, fluoro-cyano-phenyl, fluoro-methyl-phenyl,fluoro-hydroxy-phenyl, fluoro-methoxy-phenyl,fluoro-trifluoromethoxy-phenyl, chloro-hydroxyphenyl,bromo-hydroxyphenyl, nitro-methoxy-phenyl, hydroxy-nitro-phenyl,hydroxy-methyl-phenyl, hydroxy-difluoromethoxy-phenyl,hydroxy-methoxy-phenyl, dihydroxyphenyl, methoxy-trifluoromethyl-phenyl,methoxy-(chlorothiazolylmethoxy)-phenyl, or(hydroxyboryl)-methoxyphenyl; or (iv) trisubstituted C₆₋₁₄ aryl:difluoro-hydroxy-phenyl, dimethyl-methoxy-phenyl, trihydroxyphenyl,hydroxy-dimethylphenyl, hydroxy-dimethoxyphenyl, orhydroxy-methoxy-dimethylamino-phenyl.

In certain embodiments, R^(5a) is (i) phenyl or naphth-1-yl; (ii)4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl,4-pentafluorosulfanylphenyl, 4-trifluoromethylphenyl,2-thien-2-ylphenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-pyridin-2-ylphenyl, 4-(benzimidazol-1-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-(2-hydroxyethoxy)phenyl, 4-(2-hydroxyethoxy)phenyl,4-(4-fluorobenzyloxy)phenyl, 3-(pyrimidin-2-yloxy)phenyl,2-hydroxyphenyl, 4-hydroxyphenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(4-trifluoromethylpyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl,2-(hydroxycarbonylmethoxy)phenyl, or 4-methyl sulfonylphenyl; (iii)2-fluoro-6-chlorophenyl, 4-fluoro-3-cyanophenyl,4-fluoro-2-methylphenyl, 4-fluoro-2-hydroxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-methoxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-trifluoromethoxy-phenyl,2,4-dichlorophenyl, 2-chloro-6-hydroxyphenyl, 4-chloro-2-hydroxyphenyl,5-chloro-2-hydroxyphenyl, 5-bromo-2-hydroxyphenyl,2-nitro-5-hydroxyphenyl, 3-nitro-4-hydroxyphenyl,4-nitro-3-hydroxyphenyl, 5-nitro-2-hydroxyphenyl,3-nitro-4-methoxyphenyl, 5-trifluoromethyl-2-methoxyphenyl,2-hydroxy-4-methylphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl,2-hydroxy-6-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-difluoromethoxyphenyl,3-methoxy-4-(2-chlorothiazol-5-ylmethoxy)phenyl, or5-(hydroxyboryl)-2-methoxyphenyl; or (iv) 3,5-difluoro-4-hydroxyphenyl,2,4-dichloro-6-hydroxyphenyl, 2,3-dimethyl-4-methoxyphenyl,4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-2,6-dimethylphenyl,4-hydroxy-3,5-dimethylphenyl, 2,4,6-trihydroxyphenyl,3-hydroxy-4,5-dimethoxyphenyl, or4-hydroxy-5-methoxy-3-dimethylaminophenyl.

In certain embodiments, R^(5a) is heteroaryl, optionally substitutedwith one, two, three, or four substituents Q as defined herein. Incertain embodiments, R^(5a) is heteroaryl, optionally substituted withone, two, three, or four substituents Q, wherein each substituent Q isindependently selected from halo, C₁₋₆ alkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —OR^(1a), —NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a),R^(1b), and R^(1c) are each as defined herein; and wherein the alkyl,aryl, heteroaryl, and heterocyclyl are each optionally substituted withone or more substituents Q^(a) as defined herein. In certainembodiments, R^(5a) is heteroaryl, optionally substituted with one, two,three, or four substituents Q, wherein each substituent Q isindependently selected from fluoro, chloro, methyl, ethyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, methoxy, pyridinyl, tetrahydropyrrolyl, morpholinyl,amino, or phenylsulfonyl.

In certain embodiments, R^(5a) is 5- or 6-membered heteroaryl,optionally substituted with one, two, three, or four substituents Q asdefined herein. In certain embodiments, R^(5a) is 5- or 6-memberedheteroaryl, optionally substituted with one, two, three, or foursubstituents Q, wherein each substituent Q is independently selectedfrom halo, C₁₋₆ alkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, —OR^(1a),—NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein; and wherein the alkyl, aryl, heteroaryl, andheterocyclyl are each optionally substituted with one or moresubstituents Q^(a) as defined herein. In certain embodiments, R^(5a) is5- or 6-membered heteroaryl, optionally substituted with one, two,three, or four substituents Q, wherein each substituent Q isindependently selected from fluoro, chloro, methyl, ethyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, methoxy, pyridinyl, tetrahydropyrrolyl, morpholinyl,amino, or phenylsulfonyl.

In certain embodiments, R^(5a) is bicyclic heteroaryl, optionallysubstituted with one, two, three, or four substituents Q as definedherein. In certain embodiments, R^(5a) is bicyclic heteroaryl,optionally substituted with one, two, three, or four substituents Q,wherein each substituent Q is independently selected from halo, C₁₋₆alkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, —OR^(1a), —NR^(1b)R^(1c),or —S(O)₂R^(1a); wherein R^(1a), R^(1b), and R^(1c) are each as definedherein; and wherein the alkyl, aryl, heteroaryl, and heterocyclyl areeach optionally substituted with one or more substituents Q^(a) asdefined herein. In certain embodiments, R^(5a) is bicyclic heteroaryl,optionally substituted with one, two, three, or four substituents Q,wherein each substituent Q is independently selected from fluoro,chloro, methyl, ethyl, trifluoromethyl, hydroxymethyl, phenylthiomethyl,phenyl, fluorophenyl, chlorophenyl, methoxy, pyridinyl,tetrahydropyrrolyl, morpholinyl, amino, or phenylsulfonyl.

In certain embodiments, R^(5a) is furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, or4H-benzo[d][1,3]dioxinyl, each of which is optionally substituted withone, two, three, or four substituents Q as defined herein. In certainembodiments, R^(5a) is furanyl pyrrolyl, thienyl, pyrazolyl, imidazolyl,isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl, benzimidazolyl,benzo[d][1,2,3]thiadiazolyl, or 4H-benzo[d][1,3]dioxinyl, each of whichis optionally substituted with one, two, three, or four substituents Q,wherein each substituent Q is independently selected from halo, C₁₋₆alkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, —OR^(1a), —NR^(1b)R^(1c),or —S(O)₂R^(1a); wherein R^(1a), R^(1b), and R^(1c) are each as definedherein; and wherein the alkyl, aryl, heteroaryl, and heterocyclyl areeach optionally substituted with one or more substituents Q^(a) asdefined herein.

In certain embodiments, R^(5a) is furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, or4H-benzo[d][1,3]dioxinyl, each optionally substituted with one, two,three, or four substituents Q, each of which is independently selectedfrom fluoro, chloro, methyl, ethyl, trifluoromethyl, hydroxymethyl,phenylthiomethyl, phenyl, fluorophenyl, chlorophenyl, methoxy,pyridinyl, tetrahydropyrrolyl, morpholinyl, amino, or phenylsulfonyl.

In certain embodiments, R^(5a) is (i) unsubstituted heteroaryl:pyrrolyl, thienyl, imidazolyl, pyrazinyl, benzimidazolyl, orbenzo[d][1,2,3]thiadiazolyl; (ii) monosubstituted heteroaryl:(chlorophenyl)furanyl, (hydroxymethyl)furanyl, phenylsulfonyl-pyrrolyl,(pyridinyl)thienyl, (fluorophenyl)pyrazolyl, (fluorophenyl)pyrazolyl,methyl-isoxazolyl, chloro-thiazolyl, amino-thiazolyl, methyl-thiazolyl,tetrahydropyrrolyl-pyridinyl, (morpholinyl)pyridinyl, fluoro-pyridinyl,chloro-pyridinyl, methoxy-pyridinyl, methyl-indolyl, orfluoro-4H-benzo[d][1,3]dioxinyl; (iii) disubstituted heteroaryl:chloro-trifluoromethyl-pyrazolyl, ethyl-methyl-imidazolyl,phenyl-chloro-imidazolyl, dichloropyrazinyl, or chloro-methyl-indolyl;or (iv) tri- or tetra-substituted heteroaryl:methyl-phenylthiomethyl-chloro-pyrazolyl,methyl-trifluoromethyl-chloro-pyrazolyl, or tetrafluoroindolyl.

In certain embodiments, R^(5a) is 5-(4-chlorophenyl)furan-2-yl,5-(hydroxymethyl)furan-2-yl, pyrrol-2-yl, pyrrol-3-yl,1-phenylsulfonylpyrrol-2-yl, thien-2-yl, 2-(pyridin-2-yl)thien-5-yl,3-(4-fluorophenyl)pyrazol-4-yl, 3-chloro-5-trifluoromethylpyrazol-4-yl,1-methyl-3-phenylthiomethyl-5-chloropyrazol-4-yl,1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl,3-(4-fluorophenyl)pyrazol-4-yl, imidazol-4-yl,2-ethyl-5-methylimidazol-4-yl, 2-phenyl-5-chloroimidazol-4-yl,5-methylisoxazol-5-yl, 2-chloro-thiazol-5-yl, 2-aminothiazol-5-yl,4-methylthiazol-5-yl, 2-tetrahydropyrrol-1-ylpyridin-3-yl,3-tetrahydropyrrol-1-ylpyridin-5-yl, 2-(morpholin-4-yl)pyridin-5-yl,2-chloropyridin-3-yl, 2-chloropyridin-5-yl, 2-chloropyridin-6-yl,3-fluoropyridin-2-yl, 2-methoxypyridin-5-yl, pyrazin-2-yl,3,5-dichloropyrazin-2-yl, benzo[d][1,2,3]thiadiazol-5-yl,2-methylindol-3-yl, 1-methyl-2-chloroindol-3-yl,4,5,6,7-tetrafluoroindol-3-yl, 6-fluoro-4H-benzo[d][1,3]dioxin-8-yl, orbenzimidazol-2-yl.

In certain embodiments, R^(5a) is heterocyclyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(5a) isheterocyclyl, optionally substituted with one, two, three, or foursubstituents Q, wherein each substituent Q is independently selectedfrom —C(O)R^(1a), —C(O)OR^(1a), and —S(O)₂R^(1a); and R^(1a) is asdefined herein. In certain embodiments, R^(5a) is heterocyclyl,optionally substituted with one, two, three, or four substituents Q,wherein each substituent Q is independently selected from acetyl,benzyloxycarbonyl, and methylsulfonyl.

In certain embodiments, R^(5a) is monocyclic heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(5a) is monocyclic heterocyclyl, optionally substituted with one, two,three, or four substituents Q, wherein each substituent Q isindependently selected from —C(O)R^(1a), —C(O)OR^(1a), and —S(O)₂R^(1a);where R^(1a) is as defined herein. In certain embodiments, R^(5a) ismonocyclic heterocyclyl, optionally substituted with one, two, three, orfour substituents Q, wherein each substituent Q is independentlyselected from acetyl, benzyloxycarbonyl, and methylsulfonyl.

In certain embodiments, R^(5a) is 5- or 6-membered heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q. Incertain embodiments, R^(5a) is 5- or 6-membered heterocyclyl, each ofwhich is optionally substituted with one, two, three, or foursubstituents Q, wherein each substituent Q is independently selectedfrom —C(O)R^(1a), —C(O)OR^(1a), and —S(O)₂R^(1a); where R^(1a) is asdefined herein. In certain embodiments, R^(5a) is 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one, two,three, or four substituents Q, wherein each substituent Q isindependently selected from acetyl, benzyloxycarbonyl, andmethylsulfonyl.

In certain embodiments, R^(5a) is tetrahydropyrrolyl, piperidinyl, orpiperazinyl, each optionally substituted with one, two, three, or foursubstituents Q, wherein each substituent Q is independently selectedfrom —C(O)R^(1a), —C(O)OR^(1a), and —S(O)₂R^(1a); and R^(1a) is asdefined herein. In certain embodiments, R^(5a) is tetrahydropyrrolyl,piperidinyl, or piperazinyl, each optionally substituted with one, two,three, or four substituents Q, wherein each substituent Q isindependently selected from acetyl, benzyloxycarbonyl, andmethylsulfonyl. In certain embodiments, R^(5a) is(benzyloxycarbonyl)tetrahydropyrrolyl, piperidinyl,methylsulfonylpiperidinyl, or acetylpiperazinyl. In certain embodiments,R^(5a) is 1-(benzyloxycarbonyl)tetrahydropyrrol-2-yl, piperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-acetylpiperazin-1-yl.

In certain embodiments, R^(5a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from (a) halo, cyano, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl, heteroaryl, andheterocyclyl, each of which is optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(1a))OR^(1d), —C(O)R^(1a),—C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a), where R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R^(5a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q, wherein each substituent Q is independently selectedfrom fluoro, chloro, bromo, cyano, nitro, pentafluorosulfanyl, methyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, thienyl, triazolyl, pyridinyl, benzimidazolyl,methylpiperazinyl, tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy,difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenyl sulfonyl.

In certain embodiments, R^(5a) is phenyl, naphthyl, furanyl pyrrolyl,thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl,pyrazinyl, indolyl, benzimidazolyl, benzo[d][1,2,3]thiadiazolyl,4H-benzo[d][1,3]dioxinyl, tetrahydropyrrolyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q.

In certain embodiments, R^(5a) is phenyl, naphthyl, furanyl pyrrolyl,thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl,pyrazinyl, indolyl, benzimidazolyl, benzo[d][1,2,3]thiadiazolyl,4H-benzo[d][1,3]dioxinyl, tetrahydropyrrolyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from (a) halo, cyano, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl, heteroaryl, andheterocyclyl, each of which is optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(1a))OR^(1d), —C(O)R^(1a),—C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a), where R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R^(5a) is phenyl, naphthyl, furanyl pyrrolyl,thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl,pyrazinyl, indolyl, benzimidazolyl, benzo[d][1,2,3]thiadiazolyl,4H-benzo[d][1,3]dioxinyl, tetrahydropyrrolyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from fluoro, chloro, bromo, cyano, nitro,pentafluorosulfanyl, methyl, trifluoromethyl, hydroxymethyl,phenylthiomethyl, phenyl, fluorophenyl, chlorophenyl, thienyl,triazolyl, pyridinyl, benzimidazolyl, methylpiperazinyl,tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy, difluoromethoxy,trifluoromethoxy, fluorobenzyloxy, chlorothiazolylmethoxy,pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl.

In certain embodiments, R^(5c) is hydrogen. In certain embodiments,R^(5c) is halo. In certain embodiments, R^(5c) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(5c) is C₂₋₆ alkenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(5c) is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5c) is C₃₋₁₀ cycloalkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁵ is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(5c) is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R^(5d) is hydrogen. In certain embodiments,R^(5d) is halo. In certain embodiments, R^(5d) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(5d) is C₂₋₆ alkenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(5d) is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5d) is C₃₋₁₀ cycloalkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R^(5d) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5d) is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(5d) is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5d) is heterocyclyl, optionally substituted with one ormore substituents Q.

In certain embodiments, R^(5e) is hydrogen. In certain embodiments,R^(5e) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(5e) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5e) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(5e) is C₃₋₁₀ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5e) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(5e) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5e) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(5e) is heterocyclyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(5e) is —C(O)R^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R^(5e) is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5e) is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(5e) is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R^(5e) is—S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(5e) is —S(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5e) is —S(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5e) is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein.

In certain embodiments, R⁶ is cyano. In certain embodiments, R⁶ is halo.In certain embodiments, R⁶ is flouro, chloro, or bromo. In certainembodiments, R⁶ is nitro. In certain embodiments, R⁶ is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ is C₂₋₆ alkenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁶ is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁶is C₃₋₁₀ cycloalkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁶ is C₆₋₁₄ aryl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁶is C₇₋₁₅ aralkyl, optionally substituted with one or more substituentsQ. In certain embodiments, R⁶ is heteroaryl, optionally substituted withone or more substituents Q. In certain embodiments, R⁶ is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R⁶ is —B(R^(a))OR^(d), wherein R^(1a) and R^(1d)are each as defined herein. In certain embodiments, R⁶ is—B(OR^(a))OR^(d), wherein R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁶ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁶ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁶ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁶ is —C(NR^(a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R⁶ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁶ is —OC(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R⁶ is —OC(O)OR^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R⁶ is —OC(O)NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R⁶ is—OC(═NR^(a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁶ is —OS(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R⁶ is—OS(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R⁶ is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁶ is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁶ is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R⁶ is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁶ is —NR^(1a)C(O)OR^(d), wherein R^(1a)and R^(1d) are each as defined herein. In certain embodiments, R⁶ is—NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁶ is—NR^(a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R⁶ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁶ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R⁶is —NR^(a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁶ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁶ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R⁶ is —S(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁶ is—S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R⁶ is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁶ is—S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R^(1a) is hydrogen. In certain embodiments,R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(1a) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1a) is C₃₋₁₀ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1a) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1a) is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R^(1b) is hydrogen. In certain embodiments,R^(1b) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(1b) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1b) is C₃₋₁₀ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1b) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1b) is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R^(1c) is hydrogen. In certain embodiments,R^(1c) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(1c) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1c) is C₃₋₁₀ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1c) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1c) is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R^(1a) and R^(1c) together with the C and Natoms to which they are attached form heterocyclyl, optionallysubstituted with one or more substituents Q.

In certain embodiments, R^(1b) and R^(1c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R^(1d) is hydrogen. In certain embodiments,R^(1d) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(1d) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is C₂₋₆ alkynyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1d) is C₃₋₁₀ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1d) is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1d) is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 2. In certain embodiments, n is 4. In certainembodiments, n is 5.

In one embodiment,

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy areeach optionally substituted with one or more substituents Q^(a);

R^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is further optionallysubstituted with one or more substituents Q^(a); and (c)—B(R^(1a))OR^(1d), —C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c),and —S(O)₂R^(1a); and

R^(1a), R^(1b), R^(1c), R^(1d), and Q^(a) are each as defined herein.

In yet another embodiment,

R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, and methoxy; and

R^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q, wherein eachsubstituent Q is independently selected from fluoro, chloro, bromo,cyano, nitro, pentafluorosulfanyl, methyl, trifluoromethyl,hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl, chlorophenyl,thienyl, triazolyl, pyridinyl, benzimidazolyl, methylpiperazinyl,tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy, difluoromethoxy,trifluoromethoxy, fluorobenzyloxy, chlorothiazolylmethoxy,pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenyl sulfonyl.

In yet another embodiment,

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ; and

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one or more substituents Q.

In yet another embodiment,

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, halo, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxy areeach optionally substituted with one or more substituents Q^(a);

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is optionally substitutedwith one or more substituents Q^(a); and (c) —B(R^(1a))OR^(1d),—C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a);and

R^(1a), R^(1b), R^(1c), R^(1d), and Q^(a) are each as defined herein.

In yet another embodiment,

R² is cyclopropyl, cyclohexyl, phenyl, or pyridinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, and methoxy; and

R^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from fluoro,chloro, bromo, cyano, nitro, pentafluorosulfanyl, methyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, thienyl, triazolyl, pyridinyl, benzimidazolyl,methylpiperazinyl, tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy,difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl.

In still another embodiment,

R² is cyclopropyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,3,4,5-tetrachlorophenyl, 4-cyanophenyl, 4-nitrophenyl,4-t-butylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, pyridin-3-yl; and

R^(5a) is (i) phenyl or naphth-1-yl; (ii) 4-chlorophenyl, 4-cyanophenyl,4-nitrophenyl, 4-pentafluorosulfanylphenyl, 4-trifluoromethylphenyl,2-thien-2-ylphenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-pyridin-2-ylphenyl, 4-(benzimidazol-1-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-(2-hydroxyethoxy)phenyl, 4-(2-hydroxyethoxy)phenyl,4-(4-fluorobenzyloxy)phenyl, 3-(pyrimidin-2-yloxy)phenyl,2-hydroxyphenyl, 4-hydroxyphenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(4-trifluoromethylpyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl,2-(hydroxycarbonylmethoxy)phenyl, or 4-methylsulfonylphenyl; (iii)2-fluoro-6-chlorophenyl, 4-fluoro-3-cyanophenyl,4-fluoro-2-methylphenyl, 4-fluoro-2-hydroxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-methoxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-trifluoromethoxy-phenyl,2,4-dichlorophenyl, 2-chloro-6-hydroxyphenyl, 4-chloro-2-hydroxyphenyl,5-chloro-2-hydroxyphenyl, 5-bromo-2-hydroxyphenyl,2-nitro-5-hydroxyphenyl, 3-nitro-4-hydroxyphenyl,4-nitro-3-hydroxyphenyl, 5-nitro-2-hydroxyphenyl,3-nitro-4-methoxyphenyl, 5-trifluoromethyl-2-methoxyphenyl,2-hydroxy-4-methylphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl,2-hydroxy-6-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-difluoromethoxyphenyl,3-methoxy-4-(2-chlorothiazol-5-ylmethoxy)phenyl, or5-(hydroxyboryl)-2-methoxyphenyl; (iv) 3,5-difluoro-4-hydroxyphenyl,2,4-dichloro-6-hydroxyphenyl, 2,3-dimethyl-4-methoxyphenyl,4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-2,6-dimethylphenyl,4-hydroxy-3,5-dimethylphenyl, 2,4,6-trihydroxyphenyl,3-hydroxy-4,5-dimethoxyphenyl, or4-hydroxy-5-methoxy-3-dimethylaminophenyl; (v)5-(4-chlorophenyl)furan-2-yl, 5-(hydroxymethyl)furan-2-yl, pyrrol-2-yl,pyrrol-3-yl, 1-phenylsulfonylpyrrol-2-yl, thien-2-yl,2-(pyridin-2-yl)thien-5-yl, 3-(4-fluorophenyl)pyrazol-4-yl,3-chloro-5-trifluoromethylpyrazol-4-yl,1-methyl-3-phenylthiomethyl-5-chloropyrazol-4-yl,1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl,3-(4-fluorophenyl)pyrazol-4-yl, imidazol-4-yl,2-ethyl-5-methylimidazol-4-yl, 2-phenyl-5-chloroimidazol-4-yl,5-methylisoxazol-5-yl, 2-chloro-thiazol-5-yl, 2-aminothiazol-5-yl,4-methylthiazol-5-yl, 2-tetrahydropyrrol-1-ylpyridin-3-yl,3-tetrahydropyrrol-1-ylpyridin-5-yl, 2-(morpholin-4-yl)pyridin-5-yl,2-chloropyridin-3-yl, 2-chloropyridin-5-yl, 2-chloropyridin-6-yl,3-fluoropyridin-2-yl, 2-methoxypyridin-5-yl, pyrazin-2-yl,3,5-dichloropyrazin-2-yl, benzo[d][1,2,3]thiadiazol-5-yl,2-methylindol-3-yl, 1-methyl-2-chloroindol-3-yl,4,5,6,7-tetrafluoroindol-3-yl, 6-fluoro-4H-benzo[d][1,3]dioxin-8-yl, orbenzimidazol-2-yl; or (vi) 1-(benzyloxycarbonyl)tetrahydropyrrol-2-yl,piperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or4-acetylpiperazin-1-yl.

In one embodiment, provided herein is a pharmaceutically acceptable saltof:

-   3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    1;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    2;-   5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3H-pyrazole-4-carboxamide    3;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    4;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide    5;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    6;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    7;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    8; or-   3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    9;

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically solvate or hydratethereof.

In another embodiment, provided herein is an acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid,glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, (+)-L-lactic acid, (+)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid,(+)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid,undecylenic acid, of valeric acid salt of.

-   3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    1;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    2;-   5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3H-pyrazole-4-carboxamide    3;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    4;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide    5;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    6;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    7;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    8; or-   3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    9;

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically solvate or hydratethereof.

In another embodiment, provided herein is an acetic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid,hydrobromic acid, hydrochloric acid, methanesulfonic acid, oxalic acid,phosphoric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,or trifluoroacetic acid salt of:

-   3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    1;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    2;-   5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3H-pyrazole-4-carboxamide    3;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    4;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide    5;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    6;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    7;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    8; or-   3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    9;    or an enantiomer, a mixture of enantiomers, a mixture of two or more    diastereomers, a tautomer, a mixture of two or more tautomers, or an    isotopic variant thereof; or a pharmaceutically solvate or hydrate    thereof.

In another embodiment, provided herein is an acetic acid, formic acid,hydrobromic acid, hydrochloric acid, phosphoric acid, tartaric acid,trifluoroacetic acid salt of:

-   3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    1;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    2;-   5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3H-pyrazole-4-carboxamide    3;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    4;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide    5;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    6;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    7;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    8; or-   3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    9;    or an enantiomer, a mixture of enantiomers, a mixture of two or more    diastereomers, a tautomer, a mixture of two or more tautomers, or an    isotopic variant thereof; or a pharmaceutically solvate or hydrate    thereof.

In yet another embodiment, provided herein is a 3,5-diaminopyrazole saltselected from the group consisting of:

-   3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    hydrobromide;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    acetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    formic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    camphorsulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    sulfuric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    trifluoroacetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    tartaric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    methanesulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    sulfuric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    trifluoroacetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    camphorsulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    sulfuric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    tartaric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    p-toluenesulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    trifluoroacetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide,    acetic acid salt;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt and-   3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;    and enantiomers, mixtures of enantiomers, mixtures of two or more    diastereomers, tautomers, mixtures of two or more tautomers, and    isotopic variants thereof; and pharmaceutically acceptable solvates    and hydrates thereof.

In certain embodiments, the molar ratio of an acid versus a3,5-diaminopyrazole compound in a 3,5-diaminopyrazole salt providedherein is ranging from about 0.1 to about 10, from about 0.5 to about10, from 0.5 to about 5, from about 0.5 to about 3, from about 0.1 toabout 2, from about 0.5 to about 2, from about 0.8 to about 1.2, fromabout 0.2 to about 1, or from about 0.3 to about 0.5.

In certain embodiments, the molar ratio of an acid versus3,5-diaminopyrazole compound in pharmaceutically acceptable3,5-diaminopyrazole salts provided herein is about 0.1, about 0.2, about0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9,about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 2,about 2.5, or about 3.

In certain embodiments, the 3,5-diaminopyrazole salt provided herein hasa solubility ranging from about 0.01 to about 1,000 mg/mL, from about0.02 to about 500 mg/mL, from about 0.05 to about 100 mg/mL, from about0.1 to about 50 mg/mL, from about 0.1 to about 25 mg/mL, from about 0.1to about 10 mg/mL, from about 0.2 to about 10 mg/mL, from about 0.5 toabout 10 mg/mL, or from about 1 to about 10 mg/mL in water. In certainembodiments, the 3,5-diaminopyrazole salt provided herein has asolubility of about 0.05, about 0.1, about 0.2, about 0.5, about 1,about 2, about 3, about 4, or about 5 mg/mL in water.

In certain embodiments, the pharmaceutically acceptable3,5-diaminopyrazole salt provided herein is a solid. In certainembodiments, the pharmaceutically acceptable 3,5-diaminopyrazole saltprovided herein is crystalline. In certain embodiments, thepharmaceutically acceptable 3,5-diaminopyrazole salt provided herein isan amorphous solid.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

Methods of Synthesis

The pharmaceutically acceptable 3,5-diaminopyrazole salts providedherein can be prepared, isolated, or obtained by any method known to oneof skill in the art. For example, a pharmaceutically acceptable3,5-diaminopyrazole salt provided herein, e.g., a pharmaceuticallyacceptable salt of a 3,5-diaminopyrazole of Formulae I to XVII, I-a toXVII-a, I-b to XVII-b, and I-c to XVII-c, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically solvate or hydrate thereof; can be prepared via thereaction of the 3,5-diaminopyrazole with an acid, e.g., acetic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid,hydrobromic acid, hydrochloric acid, methanesulfonic acid, oxalic acid,phosphoric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,trifluoroacetic acid salt.

In one embodiment, provided herein is a method for preparing apharmaceutically acceptable 3,5-diaminopyrazole salt provided herein,e.g., a pharmaceutically acceptable salt of a 3,5-diaminopyrazole ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically solvate or hydratethereof; which comprises reacting the 3,5-diaminopyrazole compound withan acid in a solvent at a first predetermined temperature. In certainembodiments, the method further comprises a step of forming a3,5-diaminopyrazole salt solid at a second predetermined temperature.

In another embodiment, provided herein is a method for preparing apharmaceutically acceptable 3,5-diaminopyrazole salt provided herein,e.g., a pharmaceutically acceptable salt of a 3,5-diaminopyrazole ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically solvate or hydratethereof; which comprises the steps of: (a) reacting the3,5-diaminopyrazole compound with an acid in a solvent at a firstpredetermined temperature; and (b) forming 3,5-diaminopyrazole saltsolid at a second predetermined temperature.

Suitable solvents for use in preparing the pharmaceutically acceptable3,5-diaminopyrazole salts provided herein include, but are not limitedto, hydrocarbons, including petroleum ether, pentane, hexane(s),heptane, octane, isooctane, cyclopentane, cyclohexane,methylcyclohexane, benzene, toluene, xylene, tetralin, and cumene;chlorinated hydrocarbons, including dichloromethane (DCM),1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform,trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene,and trifluoromethylbenzene; alcohols, including methanol, ethanol,isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol,3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, andethyleneglycol; ethers, including diethyl ether, diisopropyl ether,methyl t-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane,bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, andanisole; ketones, including acetone, butanone, methyl ethyl ketone(MEK), methyl isopropyl ketone, methyl butyl ketone, and methyl isobutylketone (MIBK); esters, including methyl acetate, ethyl formate, ethylacetate, propyl acetate, isopropyl acetate, isobutyl acetate, and butylacetate; carbonates, including ethylene carbonate and propylenecarbonate; amides, including formamide, N,N-dimethylformamide (DMF), andN,N-dimethylacetamide; nitriles, including acetonitrile (ACN);sulfoxides, such as dimethyl sulfoxide (DMSO); sulfones, such sulfolane;nitro compounds, such as nitromethane and nitrobenzene; heterocycles,such as N-methyl pyrrolindone, 2-methyl tetrahydrofuran, tetrahydrofuran(THF), dioxane, and pyridine; carboxylic acids, such as acetic acid,trichloroacetic acid, and trifluoroacetic acid; phosphoramides, such ashexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

In one embodiment, the solvent is acetonitrile, acetone, methyl ethylketone, methyl isobutyl ketone, N,N-dimethylformamide,dimethylsulfoxide, a low alkanol (e.g., methanol, ethanol, n-propanol,isopropanol, sec-butanol, or 2-methoxyethanol), methyl acetate, ethylacetate, ethyl formate, isopropyl acetate, isobutyl acetate, chloroform,dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane,petroleum ether, hexanes, heptane, toluene, water, or a mixture thereof.In another embodiment, the solvent is a low alkanol of 1 to 5 carbons,such as methanol, ethanol, propanol, isopropanol, sec-butanol,2-methoxyethanol, or a mixture thereof. In another embodiment, thesolvent is 1,4-dioxane. In another embodiment, the solvent is ethanol.In another embodiment, the solvent is DMF.

In certain embodiments, the first predetermined temperature is rangingfrom about −10 to about 150° C., from about 10 to about 110° C., fromabout 10 to about 100° C., from about 10 to about 80° C., from about 10to about 60° C., or from about 20 to about 50° C. In certainembodiments, the first predetermined temperature is about 10, about 15,about 20, about 25, about 30, about 35, about 40, about 45, about 50,about 60, about 70, about 80, about 90, or about 100° C.

In certain embodiments, the 3,5-diaminopyrazole salt forming reaction isperformed in the presence of an excess amount of the acid to maximizethe yield of the reaction. The molar ratio of the 3,5-diaminopyrazolecompound versus the acid is ranging from about 1.01 to about 100, fromabout 1.05 to about 50, from about 1.1 to about 20, from about 1.1 toabout 10, from about 1.1 to about 8, or from about 1.2 to about 8. Insome embodiments, the molar ratio of the 3,5-diaminopyrazole compound tothe acid is about 1:8.

In certain embodiments, the 3,5-diaminopyrazole salt forming reaction isperformed in a solution, that is, both the 3,5-diaminopyrazole compoundand acid are dissolved in the solvent. In certain embodiments, the3,5-diaminopyrazole salt forming reaction is performed as a slurrymixture of the 3,5-diaminopyrazole compound and acid in the solvent. Inthis case, the 3,5-diaminopyrazole compound is not fully dissolved,whereas the acid is completely dissolved.

In certain embodiment, the pharmaceutically acceptable3,5-diaminopyrazole salt formed in the 3,5-diaminopyrazole salt formingreaction step may be precipitated out from the reaction solution orslurry mixture using conventional methods, including, but not limitedto, cooling, chilling, solvent evaporation, addition of an anti-solvent,or reverse addition to an anti-solvent. In certain embodiments, thesecond predetermined temperature is ranging from about −50 to about 100°C., from about −30 to about 90° C., from about −10 to about 80° C., orfrom about 0 to about 70° C. In certain embodiments, the firstpredetermined temperature is about −20, about −10, about 0, about 10,about 15, about 20, about 25, about 30, about 35, about 40, about 50, orabout 60° C.

In certain embodiments, the method further comprises the step of seedingthe reaction solution or mixture to accelerate the solid forming. Theamount of seed crystals added generally exceeds the saturation amount inthe solvent being used so that there are undissolved seed crystalspresent in the reaction solution. In certain embodiments, the methodfurther comprises an isolation step, in which the solid is isolated by aconventional method, such as filtration and centrifugation, followed bywashing with a solvent and then drying.

In certain embodiments, the pharmaceutically acceptable3,5-diaminopyrazole salt is precipitated by cooling the reactionsolution to or below room temperature, or by solvent evaporation. Incertain embodiments, the pharmaceutically acceptable 3,5-diaminopyrazolesalt solid is formed by adding an anti-solvent to the reaction solution,or by adding the reaction solution to an anti-solvent.

Suitable anti-solvents include, but are not limited to, hydrocarbons,including petroleum ether, pentane, hexane(s), heptane, octane,isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene,toluene, xylene, tetralin, and cumene; chlorinated hydrocarbons,including dichloromethane, 1,2-dichloroethane, 1,1-dichloroethene,1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbontetrachloride, chlorobenzene, and trifluoromethylbenzene; alcohols,including isopropanol, 1-propanol, 1-butanol, 2-butanol, t-butanol,3-methyl-1-butanol, 1-pentanol, 2-ethoxyethanol, and ethyleneglycol;ethers, including diethyl ether, diisopropyl ether, methyl t-butylether, diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether,1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones,including butanone, methyl isopropyl ketone, methyl butyl ketone, andmethyl isobutyl ketone; esters, including methyl acetate, ethyl formate,ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, andbutyl acetate; carbonates, including ethylene carbonate and propylenecarbonate; nitro compounds, including nitromethane and nitrobenzene;heterocycles; carbon sulfide; water; and mixtures thereof. In oneembodiment, the antisolvent is diethyl ether.

When two solvents are used as a solvent/anti-solvent pair, the3,5-diaminopyrazole salt has a higher solubility in the solvent than inthe anti-solvent. Optionally, the solvent and the anti-solvent in asolvent/anti-solvent pair are at least partially miscible.

Other salt forming methods may also be applicable in preparing thepharmaceutically acceptable 3,5-diaminopyrazole salts provided herein.For example, the pharmaceutically acceptable 3,5-diaminopyrazole saltsprovided herein may be prepared by converting a 3,5-diaminopyrazolesalt, e.g., a hydrochloride salt, to a 3,5-diaminopyrazole salt viaanion exchange using an anion exchange column. The pharmaceuticallyacceptable 3,5-diaminopyrazole salts provided herein may also beproduced by physically grinding a solid 3,5-diaminopyrazole compoundwith an acid together in the absence of a solvent.

In addition to precipitation and crystallization, the solidpharmaceutically acceptable 3,5-diaminopyrazole salts provided hereinmay also be prepared using conventional methods known to those skilledin the art, including, but not limited to, spray drying, roller drying,lyophilization, and melt crystallization.

In certain embodiments, provided herein is a method for preparing apharmaceutically acceptable 3,5-diaminopyrazole salt provided herein,e.g., a pharmaceutically acceptable salt of a 3,5-diaminopyrazole ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically solvate or hydratethereof; which comprises the steps of: (a) reacting a solution orsuspension of the 3,5-diaminopyrazole compound in a first solvent withan excess of a solution of an acid in a second solvent to form a clearreaction solution; and (b) adding an anti-solvent to the reactionsolution to an 3,5-diaminopyrazole salt solid. In certain embodiments,the first and second solvents are each as defined herein. In certainembodiments, the anti-solvent is as defined herein. In certainembodiments, the method further comprises the step of collecting the3,5-diaminopyrazole salt solid. In certain embodiments, the3,5-diaminopyrazole salt solid is collected by suction, followed bywashing with the anti-solvent. In certain embodiments, the methodfurther comprises the step of drying the 3,5-diaminopyrazole salt solid.In certain embodiments, the pharmaceutically acceptable3,5-diaminopyrazole salt solid is air dried.

In one embodiment, a solution or suspension of a 3,5-diaminopyrazolecompound in a first solvent is treated with a slight molar excess, inone embodiment, about 105%, of an aqueous solution of an inorganic acidor ethanolic solution of an acid that does not dissolve in water to forma clear solution after stirring at room temperature for 4 hrs, at whichtime an anti-solvent is added to the solution to precipitate the3,5-diaminopyrazole salt. In certain embodiments, the3,5-diaminopyrazole salt solids are collected by suction, rinsed withcopious amounts of the anti-solvent, and air dried.

The 3,5-diaminopyrazole compounds used herein for preparing thepharmaceutically acceptable 3,5-diaminopyrazole salts provided hereincan be prepared, isolated, or obtained by any method known to one ofskill in the art. For example, a 3,5-diaminopyrazole of Formulae I toXVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, or an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof, or a pharmaceutically solvate or hydrate thereof; can beprepared according to the methods described in U.S. patent applicationSer. No. 13/830,486, filed on Mar. 14, 2013, the disclosure of which isincorporated herein by reference in its entirety.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising apharmaceutically acceptable 3,5-diaminopyrazole salt provided herein asan active ingredient, e.g., a pharmaceutically acceptable salt of acompound of Formulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c toXVII-c, or an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, oran isotopic variant thereof; or a pharmaceutically solvate or hydratethereof; in combination with a pharmaceutically acceptable vehicle,carrier, diluent, or excipient, or a mixture thereof.

The pharmaceutically acceptable 3,5-diaminopyrazole salt provided hereinmay be administered alone, or in combination with one or more otherpharmaceutically acceptable 3,5-diaminopyrazole salts provided herein.The pharmaceutical compositions can be formulated in various dosageforms for oral, parenteral, and topical administration. Thepharmaceutical compositions can also be formulated as modified releasedosage forms, including delayed-, extended-, prolonged-, sustained-,pulsatile-, controlled-, accelerated-, fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, N.Y.,2008).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a pharmaceuticallyacceptable 3,5-diaminopyrazole salt provided herein, e.g., apharmaceutically acceptable salt of a compound of Formulae I to XVII,I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof, or a pharmaceutically solvate or hydrate thereof; and one ormore pharmaceutically acceptable excipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise apharmaceutically acceptable 3,5-diaminopyrazole salt provided herein,e.g., a pharmaceutically acceptable salt of a compound of Formulae I toXVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, or an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof; or a pharmaceutically solvate or hydrate thereof; and one ormore pharmaceutically acceptable excipients or carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise apharmaceutically acceptable 3,5-diaminopyrazole salt provided herein,e.g., a pharmaceutically acceptable salt of a compound of Formulae I toXVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, or an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof, or a pharmaceutically solvate or hydrate thereof; and one ormore pharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in a segregated unit-dosage form. Examplesof a multiple-dosage form include a vial, bottle of tablets or capsules,or bottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as 1-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided herein is a method of treating, preventing,or ameliorating one or more symptoms of a RC kinase-mediated disorder,disease, or condition in a subject, comprising administering to thesubject a pharmaceutically acceptable salt of a compound providedherein, e.g., a pharmaceutically acceptable salt of a compound ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.

In another embodiments, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition responsive to the modulation of RC kinase activity in asubject, administering to the subject a compound provided herein, e.g.,a compound of Formulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-cto XVII-c, including a stereoisomer, enantiomer, mixture of enantiomers,mixture of diastereomers, or isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

In yet another embodiments, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition responsive to the inhibition of RC kinase activity in asubject, administering to the subject a pharmaceutically acceptable saltof a compound provided herein, e.g., a pharmaceutically acceptable saltof a compound of Formulae I to XVII, I-a to XVII-a, I-b to XVII-b, andI-c to XVII-c, including a stereoisomer, enantiomer, mixture ofenantiomers, mixture of diastereomers, or isotopic variant thereof; or apharmaceutically acceptable solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of aneosinophil-related disorder, disease, or condition in a subject,comprising administering to the subject a pharmaceutically acceptablesalt of a compound provided herein, e.g., a pharmaceutically acceptablesalt of a compound of Formulae I to XVII, I-a to XVII-a, I-b to XVII-b,and I-c to XVII-c, including a stereoisomer, enantiomer, mixture ofenantiomers, mixture of diastereomers, or isotopic variant thereof; or apharmaceutically acceptable solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a basophil-relateddisorder, disease, or condition in a subject, comprising administeringto the subject a pharmaceutically acceptable salt of a compound providedherein, e.g., a pharmaceutically acceptable salt of a compound ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a mast cell-relateddisorder, disease, or condition in a subject, comprising administeringto the subject a pharmaceutically acceptable salt of a compound providedherein, e.g., a pharmaceutically acceptable salt of a compound ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.

In still another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease in a subject, comprising administering to the subject apharmaceutically acceptable salt of a compound provided herein, e.g., apharmaceutically acceptable salt of a compound of Formulae I to XVII,I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.

In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

The disorders, diseases, or conditions treatable with a pharmaceuticallyacceptable salt of a compound provided herein, e.g., a pharmaceuticallyacceptable salt of a compound of Formulae I to XVII, I-a to XVII-a, I-bto XVII-b, and I-c to XVII-c, including a stereoisomer, enantiomer,mixture of enantiomers, mixture of diastereomers, or isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; include, but are not limited to, (1) inflammatory orallergic diseases, including systemic anaphylaxis and hypersensitivitydisorders, atopic dermatitis, urticaria, drug allergies, insect stingallergies, food allergies (including celiac disease and the like), andmastocytosis; (2) inflammatory bowel diseases, including Crohn'sdisease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, andBehcet's syndrome; (4) psoriasis and inflammatory dermatoses, includingdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, viral cutaneous pathologies including those derived fromhuman papillomavirus, HIV or RLV infection, bacterial, flugal, and otherparasital cutaneous pathologies, and cutaneous lupus erythematosus; (5)asthma and respiratory allergic diseases, including allergic asthma,exercise induced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the disorder, disease, or condition is selectedfrom the group consisting of asthma, allergic asthma, exercise inducedasthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity, contactdermatitis, conjunctivitis, allergic conjunctivitis, eosinophilicbronchitis, food allergies, eosinophilic gastroenteritis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, mastocytosis, hyperIgE syndrome, systemic lupus erythematous, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, chronic obstructivepulmonary disease (COPD), Churg-Strauss syndrome, sinusitis, basophilicleukemia, chronic urticaria, basophilic leukocytosis, eczema, arthritis,rheumatoid arthritis, psoriatic arthritis, and osteoarthritis.

In certain embodiments, the disorder, disease, or condition is asthma,exercise induced asthma, allergic rhinitis, atopic dermatitis, chronicobstructive plumonary disease, or allergic conjunctivitis. In certainembodiments, the disorder, disease, or condition is COPD.

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided herein is administration of thecompounds or pharmaceutical compositions provided herein in a depotformulation, in which the active ingredient is released over apredefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofthe disorders, diseases, and conditions, an appropriate dosage levelgenerally is ranging from about 0.001 to 100 mg per kg subject bodyweight per day (mg/kg per day), from about 0.01 to about 75 mg/kg perday, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which canbe administered in single or multiple doses. Within this range, thedosage can be ranging from about 0.005 to about 0.05, from about 0.05 toabout 0.5, from about 0.5 to about 5.0, from about 1 to about 15, fromabout 1 to about 20, or from about 1 to about 50 mg/kg per day. Incertain embodiments, the dosage level is ranging from about 0.001 toabout 100 mg/kg per day. In certain embodiments, the dosage level isranging from about 0.01 to about 75 mg/kg per day. In certainembodiments, the dosage level is ranging from about 0.1 to about 50mg/kg per day. In certain embodiments, the dosage level is ranging fromabout 0.5 to about 25 mg/kg per day. In certain embodiments, the dosagelevel is ranging from about 1 to about 20 mg/kg per day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

In one embodiment, provided herein are methods of modulating RC kinaseactivity, comprising contacting a RC kinase with a pharmaceuticallyacceptable salt of a compound provided herein, e.g., a pharmaceuticallyacceptable salt of a compound of Formulae I to XVII, I-a to XVII-a, I-bto XVII-b, and I-c to XVII-c, including a stereoisomer, enantiomer,mixture of enantiomers, mixture of diastereomers, or isotopic variantthereof, or a pharmaceutically acceptable solvate, hydrate, or prodrugthereof. In one embodiment, the RC kinase is expressed by a cell.

The pharmaceutically acceptable salts of compounds provided herein,e.g., pharmaceutically acceptable salts of compounds of Formulae I toXVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; can also be combined orused in combination with other agents useful in the treatment,prevention, or amelioration of one or more symptoms of the disorders,diseases, or conditions for which the compounds provided herein areuseful, including, but not limited to, asthma, COPD, allergic rhinitis,eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupuserythematosus, diabetes, rheumatoid arthritis, multiple sclerosis,atherosclerosis, transplant rejection, inflammatory bowel disease,cancer, infectious diseases, and those pathologies noted herein.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or more steroidaldrugs known in the art, including, but not limited to, aldosterone,beclometasone, betamethasone, deoxycorticosterone acetate,fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone,methylprednisolone, dexamethasone, and triamcinolone.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or more antibacterialagents known in the art, including, but not limited to, amikacin,amoxicillin, ampicillin, arsphenamine, azithromycin, aztreonam,azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil,cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime,cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clindamycin,cloxacillin, colistin, dalfopristin, demeclocycline, dicloxacillin,dirithromycin, doxycycline, erythromycin, enrofloxacin, ertepenem,ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin,geldanamycin, gentamicin, herbimycin, imipenem, isoniazid, kanamycin,levofloxacin, linezolid, lomefloxacin, loracarbef, mafenide,moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline,mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, norfloxacin,ofloxacin, oxytetracycline, penicillin, piperacillin, platensimycin,polymyxin B, prontocil, pyrazinamide, quinupristine, rifampin,roxithromycin, spectinomycin, streptomycin, sulfacetamide,sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin,tetracycline, ticarcillin, tobramycin, trimethoprim, troleandomycin,trovafloxacin, and vancomycin.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or more antifungalagents known in the art, including, but not limited to, amorolfine,amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole,caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole,filipin, fluconazole, isoconazole, itraconazole, ketoconazole,micafungin, miconazole, naftifine, natamycin, nystatin, oxyconazole,ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole,terbinafine, terconazole, tioconazole, and voriconazole.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or moreanticoagulants known in the art, including, but not limited to,acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux,heparin, phenindione, warfarin, and ximelagatran.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or more thrombolyticsknown in the art, including, but not limited to, anistreplase,reteplase, t-PA (alteplase activase), streptokinase, tenecteplase, andurokinase.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or more non-steroidalanti-inflammatory agents known in the art, including, but not limitedto, aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone,benorilate, bromfenac, carprofen, celecoxib, choline magnesiumsalicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine,fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen,ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid,mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesiumsalicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone,parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac,sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin.

In certain embodiments, the pharmaceutically acceptable salts ofcompounds provided herein can be combined with one or more antiplateletagents known in the art, including, but not limited to, abciximab,cilostazol, clopidogrel, dipyridamole, ticlopidine, and tirofibin.

The pharmaceutically acceptable salts of compounds provided herein canalso be administered in combination with other classes of compounds,including, but not limited to, (1) alpha-adrenergic agents; (2)antiarrhythmic agents; (3) anti-atherosclerotic agents, such as ACATinhibitors; (4) antibiotics, such as anthracyclines, bleomycins,mitomycin, dactinomycin, and plicamycin; (5) anticancer agents andcytotoxic agents, e.g., alkylating agents, such as nitrogen mustards,alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6)anticoagulants, such as acenocoumarol, argatroban, bivalirudin,lepirudin, fondaparinux, heparin, phenindione, warfarin, andximelagatran; (7) anti-diabetic agents, such as biguanides (e.g.,metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thepharmaceutically acceptable salts of compounds provided herein, e.g., apharmaceutically acceptable salt of a compound of Formula IA, includinga stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof. When a compoundprovided herein is used contemporaneously with one or more other drugs,a pharmaceutical composition containing such other drugs in addition tothe compound provided herein can be utilized, but is not required.Accordingly, the pharmaceutical compositions provided herein includethose that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound provided herein.

The weight ratio of a pharmaceutically acceptable salt of a compoundprovided herein to the second active ingredient can be varied, and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundprovided herein is combined with a NSAID, the weight ratio of thecompound to the NSAID can range from about 1,000:1 to about 1:1,000, orabout 200:1 to about 1:200. Combinations of a pharmaceuticallyacceptable salt of a compound provided herein and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

The pharmaceutically acceptable salts of compounds provided herein canalso be provided as an article of manufacture using packaging materialswell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceuticalpackaging materials include, but are not limited to, blister packs,bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of apharmaceutically acceptable salt of a compound provided herein, e.g., apharmaceutically acceptable salt of a compound of Formulae I to XVII,I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the pharmaceutically acceptable salt of a compound providedherein, e.g., a pharmaceutically acceptable salt of a compound ofFormulae I to XVII, I-a to XVII-a, I-b to XVII-b, and I-c to XVII-c,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof, in a containercomprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC(thin layer chromatography); and HPLC (high pressure liquidchromatography).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 Preparation of a 3,5-diaminopyrazole salt

A stirring solution of a free base 3,5-diaminopyrazole compound (2 mL,100 mg/mL) in 1,4-dioxane was treated with a solution of an acid (8.0eq., 1.0 N) in 1,4-dioxane. The reaction mixture was heated at 60° C.and stirred for 1 hr, and then allowed to stir at room temperatureovernight. If precipitate was formed, the suspension was filtered, andthe residue was washed with diethyl ether to obtain the salt product. Ifno precipitate had formed, 2 mL of diethyl ether was added to thereaction mixture, and the resulting solids were isolated by suctionfiltration. The obtained product was characterized by melting point. Ifsalt formation was not successful in 1,4-dioxane for a certaincounter-ion, the above procedures were repeated using either ethanol orDMF as the solvent for salt formation. The exemplary salts providedherein are comprised of a 1:1 ratio of freebase to acid, as confirmed byNMR spectroscopy.

The following 3,5-diaminopyrazole salts were prepared using the methoddescribed in this example:

-   3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    hydrobromide;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    acetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    formic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    camphorsulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    sulfuric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    trifluoroacetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3H-pyrazole-4-carboxamide,    tartaric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    methanesulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    sulfuric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3H-pyrazole-4-carboxamide,    trifluoroacetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    camphorsulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    sulfuric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    tartaric acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    p-toluenesulfonic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    trifluoroacetic acid salt;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide,    acetic acid salt;-   3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide,    phosphoric acid salt and-   3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide    hydrochloride;    and enantiomers, mixtures of enantiomers, mixtures of two or more    diastereomers, tautomers, mixtures of two or more tautomers, and    isotopic variants thereof; and pharmaceutically acceptable solvates    and hydrates thereof.

Example 2 Synthesis of3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide1

Dissolved 7.00 g (2-cyano-3,3-bis(methylthio)acrylamide) in 125 mL ofethanol. Then added 4.348 mL (1.10 eq.) of 3-chloroaniline to thereaction vessel and stirred the reaction at 75° C. until starting amidewas absent and confirmed by HPLC. Once complete (18 hrs), the reactionwas brought to room temperature and filtered to obtain3-((3-chlorophenyl)amino)-2-cyano-3-(methylthio)acrylamide as an offwhite to light yellow powder. Product was allowed to dry under vacuumfor 1 hr (6.0 g, 57% yield).

3-((3-chlorophenyl)amino)-2-cyano-3-(methylthio)acrylamide

3-((3-chlorophenyl)amino)-2-cyano-3-(methylthio)acrylamide (6.00 g) wassuspended in 100 mL of ethanol and hydrazine hydrate (1.478 mL, 1.5 eq.)was added drop wise to the reaction. Reaction was then heated at 75° C.until the starting material was no longer present and confirmed viaHPLC. Once starting material was absent (18 hrs), reaction was broughtto room temperature and filtered to obtain5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide as an offwhite to yellow powder. Product was allowed to dry under vacuum for 1 hr(4.40 g, 83% yield).

5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide

5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (4.40 g) wassuspended in 125.00 mL of ethanol and 4-hydroxybenzaldehyde (4.273, 1.5eq.) and piperidine (0.50 eq, 865 μL) was added. Stirred the reaction atreflux until starting material was absent and confirmed by HPLC. Afterreaction was complete (18 hrs) it was brought to room temperature andfiltered to obtain3-((3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamideas a yellow to orange powder. The product was washed with ethanol toremove any excess 4-hydroxybenzaldehyde. Product was allowed to dryunder vacuum for 1 hr (4.00 g, 65% yield).

3-((3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide

3-((3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide(2.10 g) was suspended in 50 mL of MeOH and sodium borohydride was addeduntil bubbling ceased and then heated to 50° C. HPLC confirmed reactionwas complete (absence of imine). Once completed (1 hr), reaction cooledto room temperature, precipitate was filtered to obtain 1 as an offwhite to light yellow powder as product. Product was washed withdeionized water to remove excess sodium borohydride. Product was allowedto dry under vacuum for 18 hrs. 85 mg (83% yield) of final product wasobtained. (1.700 g, 81% yield). Various salts were prepared using theprocedures described in Example 1.

Example 3 Synthesis of5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3H-pyrazole-4-carboxamide2

Compound 2 was prepared in an analogous method to that shown in Example2. Various salts of compound 2 were prepared using the proceduresdescribed in Example 1.

Example 4 Synthesis of5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-1H-pyrazole-4-carboxamide4

Dissolved 2-cyano-3,3-bis(methylthio)acrylamide in ethanol. Then added(1.10 eq.) of 4-(morpholinomethyl)aniline to the reaction vessel andstirred the reaction at 75° C. until starting amide was absent andconfirmed by HPLC. Once complete (18 hrs), the reaction was brought toroom temperature and filtered to obtain an off white to light yellowpowder as product. Product was allowed to dry under vacuum for 1 hr.

Intermediate was suspended in ethanol and hydrazine hydrate (1.5 eq.)was added drop wise to the reaction. Reaction was then heated at 75° C.until the starting material was no longer present and confirmed viaHPLC. Once starting material was absent (18 hrs), reaction was broughtto room temperature and filtered to obtain a off white to yellow powderas product. Product was allowed to dry under vacuum for 1 hr.

Second intermediate was suspended in ethanol and 4-hydroxybenzaldehyde(1.5 eq.) and piperidine (0.50 eq.) was added. Stirred the reaction atreflux until starting material was absent and confirmed by HPLC. Afterreaction was complete (18 hrs) it was brought to room temperature andfiltered to obtain product as a yellow to orange powder. The product waswashed with ethanol to remove any excess 4-hydroxybenzaldehyde. Productwas allowed to dry under vacuum for 1 hr.

Imine was suspended in MeOH and sodium borohydride was added untilbubbling ceased and then heated to 60° C. HPLC confirmed reaction wascomplete (absence of imine). Once completed (1 hr), reaction cooled toroom temperature, precipitate was filtered to obtain 3 as an off whiteto light yellow powder. Product was washed with deionized water toremove excess sodium borohydride. Product was allowed to dry undervacuum for 18 hrs. Various salts were prepared using the proceduresdescribed in Example 1.

Example 5 Synthesis of5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide4

Compound 4 was prepared in an analogous method to that shown in Example2. Various salts of compound 4 were prepared using the proceduresdescribed in Example 1. For example, the hydrochloride salt of compound4 was formed as described in Example 1 using 1,4-dioxane as the solventfor salt formation. The hydrobromide salt of compound 4 was formed asdescribed in Example 1 using 1,4-dioxane as the solvent for saltformation. The acetic acid salt of compound 4 was formed as described inExample 1 using 1,4-dioxane as the solvent for salt formation. Theformic acid salt of compound 4 was formed as described in Example 1using 1,4-dioxane as the solvent for salt formation. The formic acidsalt of compound 4 was formed as described in Example 1 using1,4-dioxane as the solvent for salt formation.

Example 6 Synthesis of5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide5

Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOHand added 4-(5-amino-2-pyridinyl)morpholine (1.0 eq.). Stirred reactionat 75° C. until starting amide was absent by HPLC. Once complete (18hrs), reaction was brought to room temperature and filtered to obtain alight yellow powder as product. Product was allowed to dry under vacuumfor 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate(1 eq.) was added dropwise. Reaction was heated at 75° C. untilintermediate was absent (HPLC). Once intermediate was absent (18 hrs),reaction was brought to room temperature and filtered to obtain5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide asa yellow powder. Product was allowed to dry under vacuum for 1 hr.

5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide

5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (1 eq.) andpiperidine (2 drops) were added. Stirred at reflux until intermediatewas absent (HPLC). After reaction was complete (18 hrs) it was broughtto room temperature and filtered to obtain product as a yellow powder.Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde.Product was allowed to dry under vacuum for 1 hr. Resulting imine (200mg) was suspended in 5 mL MeOH and sodium borohydride was added untilbubbling ceased. HPLC confirmed reaction was complete (absence ofimine). Once complete (1 hr), precipitate was filtered to obtain 5 as alight yellow powder as product. Product was washed with deionized waterto remove excess sodium borohydride. Product was allowed to dry undervacuum for 18 hrs. 130 mg (65% yield) of final product was obtained.Various salts were prepared using the procedures described in Example 1.For example, the hydrochloride salt of compound 5 was formed asdescribed in Example 1 using ethanol as the solvent for salt formation.The trifluoroacetic acid salt of compound 5 was formed as described inExample 1 using ethanol as the solvent for salt formation.

Example 7 Synthesis of5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3H-pyrazole-4-carboxamide6

Compound 6 was prepared in an analogous method to that shown in Example2. Various salts of compound 6 were prepared using the proceduresdescribed in Example 1. For example, the phosphoric acid salt ofcompound 6 was formed as described in Example 1 using ethanol as thesolvent for salt formation.

Example 8 Synthesis of5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide7

Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOHand added 4-(4-(2-propyl)-piperazin-1-yl)aniline (1.0 eq.). Stirredreaction at 75° C. until starting amide was absent by HPLC. Oncecomplete (18 hrs), reaction was brought to room temperature and filteredto obtain2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamideas a purple powder. Product was allowed to dry under vacuum for 1 hr.

2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamide

2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamidewas then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was addeddropwise. Reaction was heated at 75° C. until intermediate was absent(HPLC). Once intermediate was absent (18 hrs), reaction was brought toroom temperature and filtered to obtain5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamideas a purple powder. Product was allowed to dry under vacuum for 1 hr.

5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide

5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(200 mg) was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (1eq.) and piperidine (2 drops) were added. Stirred at reflux untilintermediate was absent (HPLC). After reaction was complete (18 hrs) itwas brought to room temperature and filtered to obtain product as ayellow powder. Powder was washed with EtOH to remove any excess4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.

5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide

5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(100 mg) was suspended in 5 mL MeOH and sodium borohydride was addeduntil bubbling ceased. HPLC confirmed reaction was complete (absence ofimine). Once complete (1 hr), precipitate was filtered to obtain 7 as alight yellow powder. Product was washed with deionized water to removeexcess sodium borohydride. Product was allowed to dry under vacuum for18 hrs. 80 mg (77% yield) of final product was obtained. Various saltswere prepared using the procedures described in Example 1. For example,the hydrochloride salt of compound 7 was formed as described in Example1 using DMF as the solvent for salt formation. The phosphoric acid saltof compound 7 was formed as described in Example 1 using DMF as thesolvent for salt formation.

Example 9 Synthesis of3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3H-pyrazole-4-carboxamide8

Compound 8 was prepared in an analogous method to that shown in Example2. Various salts of compound 8 were prepared using the proceduresdescribed in Example 1. For example, the hydrochloride salt of compound8 was formed as described in Example 1 using DMF as the solvent for saltformation

Example 10 Synthesis of3-((1H-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide9

Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOHand added 5-Aminoindazole (1.0 eq.). Stirred reaction at 75° C. untilstarting amide was absent by HPLC. Once complete (18 hrs), reaction wasbrought to room temperature and filtered to obtain a light yellow powderas product. Product was allowed to dry under vacuum for 1 hr. Productwas then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was addeddropwise. Reaction was heated at 75° C. until intermediate was absent(HPLC). Once intermediate was absent (18 hrs), reaction was brought toroom temperature and filtered to obtain a yellow powder as product.Product was allowed to dry under vacuum for 1 hr.

3-((1H-indazol-5-yl)amino)-5-amino-1H-pyrazole-4-carboxamide

3-((1H-indazol-5-yl)amino)-5-amino-1H-pyrazole-4-carboxamide was thensuspended in 8 mL EtOH and 4-hydroxybenzaldehyde (1 eq.) and piperidine(2 drops) were added. Stirred at reflux until intermediate was absent(HPLC). After reaction was complete (18 hrs) it was brought to roomtemperature and filtered to obtain product as a yellow powder. Powderwas washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Productwas allowed to dry under vacuum for 1 hr. Resulting imine (100 mg) wassuspended in 5 mL MeOH and sodium borohydride was added until bubblingceased. HPLC confirmed reaction was complete (absence of imine). Oncecomplete (1 hr), precipitate was filtered to obtain 9 as a light yellowpowder. Product was washed with deionized water to remove excess sodiumborohydride. Product was allowed to dry under vacuum for 18 hrs. 47 mg(45% yield) of final product was obtained. Various salts were preparedusing the procedures described in Example 1. For example, thehydrochloride salt of compound 9 was formed as described in Example 1using DMF as the solvent for salt formation.

Solubility assessment: A preweighed amount of powder of a salt wastreated with water to target a nominal concentration of 10 mg/mL. If aclear solution was obtained, then the solubility was noted as ≧10 mg/mL.If a suspension was obtained, additional water was added to target anominal concentration of 5 mg/mL. If still a suspension after theaddition of water, additional water was added to target a lower nominalconcentration. If a suspension was still observed at a nominalconcentration of 0.1 mg/mL, the suspension was filtered through a 0.4micron filter, and the filtrate was analyzed by RP-HPLC to ascertain thesolubility range of the salt. The solubilities of the salts describedherein in water are summarized in Table 1.

Melting point analysis: A sample a salt was placed in a microcapillarytube. Melting point ranges were determined on a Optimelt (StanfordReseach Systems) Melting point apparatus. The melting point ranges ofvarious salts are summarized in Table 2.

Example 11 Enzymatic Assays for Kinase Inhibitory Activity

Solutions of a test compound, Crebtide (a substrate), a kinase, and ATPwere prepared using 1×MAPK Buffer (50 mM HEPES, 1 mM EGTA, 10 mM EGTA,10 mM MgCl₂, 2 mM DTT, and 0.01% Tween 20). The test compound solutionhad a concentration of either 10 μM or 10×IC₅₀ of the compound. TheCrebtide solution had a concentration of 200 nM. The kinase domainprotein of RC kinase had a concentration of 3 mg/mL. The full-lengthkinase protein of RC kinase had a concentration of 40 mg/mL. ATP had aconcentration of 4 μM when the kinase doman protein was used or 12 μMwhen the full-length protein was used in the assay.

To each well, the test compound (1 μL) was first added (in duplicate) toreach a final concentration of 1 μM or 1×IC₅₀ of the compound. Thekinase (5 μL) was then added to each well to reach a final concentrationof 1 mg/mL for the kinase domain or 20 mg/mL for the full-length domain.Each plate included a positive and negative controls in duplicate wells.Crebtide (2.5 μL) was then added to each well in duplicate to reach afinal concentration of 50 nM. If the full-length kinase was used, theplates were incubated for 45 min at room temperature before proceedingfurther. ATP (2.5 μL) was added to each well to reach a finalconcentration of 1 M for the kinase domain and 3 M for the full-length.

After the addition of ATP, the plates were incubated for 45 min at roomtemperature. During the incubation, an EDTA solution (40 mM) andanti-Crebtide (16 mM) were prepared. Additionally, a detection bufferstock solution was diluted ten fold before use.

After the incubation, the anti-Crebtide (5 μL) and EDTA (5 μL) wereadded to each well to reach their final concentrations of 4 mM and 10mM, respectively. The plates were allowed to develop at room temperaturefor 45 min. The plates were then read at 665 nm and 615 nm using PerkinElmer Lance machine.

The biological results of inhibition of the kinase domain protein of RCkinase by selected free base compounds are summarized in Table 3,wherein A represents at least 50% inhibition of the RC knase activity at1 μM; B represents no greater than 50% but at least 20% inhibition ofthe RC knase activity at 1 μM; C represents no greater than 20% but atleast 5% inhibition of the RC knase activity at 1 μM; and D representsno greater than 5% inhibition of the RC knase activity at 1 μM. As willbe appreciated by those skilled in the are, the activity of a particularsalt provided herein will be the same as the activity for the parentfree-base compound.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

TABLE 1A Aqueous Solubility (mg/mL) acetic camphorsulfonic formic Freeacid acid acid Compound base salt salt salt HBr HCl

<0.04 >0.063

<0.04 >1

<0.04 >0.5

<0.1 <0.5 <0.2 <0.5 >10 >10

<0.1 >2

<0.1 <0.5

<0.04 >0.5

<0.04 >0.5

<0.04 <0.10

TABLE 1B Aqueous Solubility (mg/mL) p- Trifluoro- Methane PhosphoricSulfuric tartaric toluenesulfonic acetic sulfonic acid acid acid acidacid Compound acid salt salt salt salt salt salt

<0.2 >2.0 <0.2

>10 >0.1 >0.01 >1

>20 <0.5 <0.2 <0.2 <0.5

>1

>1

TABLE 2A Meting Point (° C.) acetic camphosulfonic formic Free acid acidacid Compound base salt salt salt HBr HCl

196- 200 

199- 205 

196- 200 

186- 189  195-199 194- 197  216- 219  218- 221 

209- 212  210- 215 

206- 210 

210- 220  237- 241 

228- 231  >300

250- 260  177- 180 

TABLE 2B Meting Point (° C.) Methane p- Trifluoro- sulfonic PhosphoricSulfuric tartaric toluenesulfonic acetic acid acid acid acid acid acidCompound salt salt salt salt salt salt

156-162

180-184

135-138

177-183

TABLE 3 Kinase Inhibitory Activity Compound Activity

A

A

A

A

A

A

A

A

A

What is claimed is:
 1. A method for the treatment, prevention, oramelioration of one or more symptoms of a RC kinase-mediated disorder,disease, or condition in a subject, which comprises administering to thesubject acetic acid, camphorsulfonic acid, citric acid, ethanesulfonicacid, formic acid, hydrobromic acid, hydrochloric acid, methanesulfonicacid, oxalic acid, phosphoric acid, sulfuric acid, tartaric acid,p-toluenesulfonic acid, or trifluoroacetic acid salt of a compound ofFormula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: R¹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁴ is cyano, aminocarbonyl,—C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b); wherein: R^(4a) is C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; and R^(4b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))R^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; and R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);and each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a) oxo,cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl,each of which is further optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyl-C₁₋₆ alkyl, each optionally substituted with one or moresubstituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —SF₅,—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 2. The method of claim 1, having thestructure of Formula I:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.
 3. The method of claim1, having the structure of Formula XIII:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.
 4. The method of claim1, wherein R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl, each ofwhich is optionally substituted with one, two, three, four, or fivesubstituents Q.
 5. The method of claim 1, wherein R² is C₃₋₁₀cycloalkyl, optionally substituted with one or more substituents Q. 6.The method of claim 1, wherein R² is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionallysubstituted with one or more substituents Q.
 7. The method of claim 1,wherein R² is cyclopropyl or cyclohexyl, each of which is optionallysubstituted with one or more substituents Q.
 8. The method of claim 1,wherein R² is heteroaryl, optionally substituted with one or moresubstituents Q.
 9. The method of claim 8, wherein R² is 5- or 6-memberedheteroaryl, each of which is optionally substituted with one or moresubstituents Q.
 10. The method of claim 8, wherein R² is pyridinyl,optionally substituted with one or more substituents Q.
 11. The methodof claim 1, wherein R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, or heteroaryl,each of which is optionally substituted with one, two, three, four, orfive substituents Q, wherein each substituent Q is independentlyselected from cyano, nitro, halo, heteroaryl, heterocyclyl, C₁₋₆ alkyl,and C₁₋₆ alkoxy, where the alkyl and alkoxy are each optionallysubstituted with one or more substituents Q^(a).
 12. The method of claim11, wherein each substituent Q is independently selected from cyano,nitro, chloro, methyl, butyl, methoxy, 4-methylpiperazin-1-yl,morpholinomethyl, morpholino, pyridin-2-yl, 4-isopropylpiperazin-1-yl,and 1H-imidazol-1-yl.
 13. The method of claim 1, wherein R² iscyclopropyl, cyclohexyl, phenyl, pyridinyl or 1H-indazol-5-yl, each ofwhich is optionally substituted with one, two, three, four, or fivesubstituents Q.
 14. The method of claim 13, wherein each substituent Qis independently selected from cyano, nitro, halo, heteroaryl,heterocyclyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, where the alkyl and alkoxyare each optionally substituted with one or more substituents Q^(a). 15.The method of claim 13, wherein each substituent Q is independentlyselected from cyano, nitro, chloro, methyl, butyl, methoxy,4-methylpiperazin-1-yl, morpholinomethyl, morpholino, pyridin-2-yl,4-isopropylpiperazin-1-yl, and 1H-imidazol-1-yl.
 16. The method of claim13, wherein R² is cyclopropyl, cyclohexyl, phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,3,4,5-tetrachlorophenyl, 4-cyanophenyl, 4-nitrophenyl,4-t-butylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, pyridin-3-yl,4-(4-methylpiperazin-1-yl)phenyl, 4-(morpholinomethyl)phenyl,4-morpholinophenyl, 4-(pyridin-2-yl)phenyl,4-(4-isopropylpiperazin-1-yl)phenyl, or 4-(1H-imidazol-1-yl)phenyl. 17.The method of claim 1, wherein R² is C₆₋₁₄ aryl, optionally substitutedwith one or more substituents Q.
 18. The method of claim 17, having thestructure of Formula IV:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: each R⁶ isindependently (a) cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one or more substituents Q;or (c) —B(R^(1a))OR^(1d), —B(OR^(1a))OR^(1d), —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and n is an integer of 0, 1,2, 3, 4, or
 5. 19. The method of claim 18, having the structure ofFormula XV:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof.
 20. The method of claim1, wherein R^(5c) is hydrogen.
 21. The method of claim 1, wherein R^(5d)is hydrogen.
 22. The method of claim 1, wherein R^(5a) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q.
 23. The method of claim 1, whereinR^(5a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ, wherein each substituent Q is independently selected from (a) halo,cyano, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, each of which is further optionallysubstituted with one or more substituents Q; and (c) —B(R^(1a))OR^(1d),—C(O)R^(1a), —C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a).24. The method of claim 23, wherein each substituent Q is independentlyselected from fluoro, chloro, bromo, cyano, nitro, pentafluorosulfanyl,methyl, trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl,fluorophenyl, chlorophenyl, thienyl, triazolyl, pyridinyl,benzimidazolyl, methylpiperazinyl, tetrahydropyrrolyl, morpholinyl,hydroxyl, methoxy, difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl.
 25. The method of claim 22, whereinR^(5a) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q.
 26. The method of claim 25, wherein R^(5a) is phenyl ornaphthyl, each of which is optionally substituted with one or moresubstituents Q.
 27. The method of claim 22, wherein R^(5a) isheteroaryl, optionally substituted with one or more substituents Q. 28.The method of claim 27, wherein R^(5a) is furanyl pyrrolyl, thienyl,pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl,indolyl, benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, or4H-benzo[d][1,3]dioxinyl, each of which is optionally substituted withone or more substituents Q.
 29. The method of claim 22, wherein R^(5a)is heterocyclyl, optionally substituted with one or more substituents Q.30. The method of claim 29, wherein R^(5a) is tetrahydropyrrolyl,piperidinyl, or piperazinyl, each of which is optionally substitutedwith one or more substituents Q.
 31. The method of claim 22, whereinR^(5a) is phenyl, naphthyl, furanyl pyrrolyl, thienyl, pyrazolyl,imidazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl, indolyl,benzimidazolyl, benzo[d][1,2,3]thiadiazolyl, 4H-benzo[d][1,3]dioxinyl,tetrahydropyrrolyl, piperidinyl, or piperazinyl, each of which isoptionally substituted with one, two, three, four, or five substituentsQ.
 32. The method of claim 31, wherein each substituent Q isindependently selected from (a) halo, cyano, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₆₋₁₄ aryl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more substituents Q; and (c) —B(R^(1a))OR^(1d), —C(O)R^(1a),—C(O)OR^(1a), —OR^(1a), —NR^(1b)R^(1c), and —S(O)₂R^(1a).
 33. The methodof claim 31, wherein each substituent Q is independently selected fromfluoro, chloro, bromo, cyano, nitro, pentafluorosulfanyl, methyl,trifluoromethyl, hydroxymethyl, phenylthiomethyl, phenyl, fluorophenyl,chlorophenyl, thienyl, triazolyl, pyridinyl, benzimidazolyl,methylpiperazinyl, tetrahydropyrrolyl, morpholinyl, hydroxyl, methoxy,difluoromethoxy, trifluoromethoxy, fluorobenzyloxy,chlorothiazolylmethoxy, pyrimidinyloxy, trifluoromethylpyrimidinyloxy,trifluoromethylpyridinyloxy, hydroxyethoxy, hydroxycarbonylmethoxy,amino, dimethylamino, hydroxyboryl, acetyl, benzyloxycarbonyl,methylsulfonyl, and phenylsulfonyl.
 34. The method of claim 22, whereinR^(5a) is (i) phenyl or naphth-1-yl; (ii) 4-chlorophenyl, 4-cyanophenyl,4-nitrophenyl, 4-pentafluorosulfanylphenyl, 4-trifluoromethylphenyl,2-thien-2-ylphenyl, 4-(4H-1,2,4-triazol-4-yl)phenyl,4-pyridin-2-ylphenyl, 4-(benzimidazol-1-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-(2-hydroxyethoxy)phenyl, 4-(2-hydroxyethoxy)phenyl,4-(4-fluorobenzyloxy)phenyl, 3-(pyrimidin-2-yloxy)phenyl,2-hydroxyphenyl, 4-hydroxyphenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(4-trifluoromethylpyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl, 4-(pyrimidin-2-yloxy)phenyl,4-(5-trifluoromethylpyridin-2-yloxy)phenyl,2-(hydroxycarbonylmethoxy)phenyl, or 4-methylsulfonylphenyl; (iii)2-fluoro-6-chlorophenyl, 4-fluoro-3-cyanophenyl,4-fluoro-2-methylphenyl, 4-fluoro-2-hydroxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-methoxyphenyl,5-fluoro-2-methoxyphenyl, 3-fluoro-4-trifluoromethoxy-phenyl,2,4-dichlorophenyl, 2-chloro-6-hydroxyphenyl, 4-chloro-2-hydroxyphenyl,5-chloro-2-hydroxyphenyl, 5-bromo-2-hydroxyphenyl,2-nitro-5-hydroxyphenyl, 3-nitro-4-hydroxyphenyl,4-nitro-3-hydroxyphenyl, 5-nitro-2-hydroxyphenyl,3-nitro-4-methoxyphenyl, 5-trifluoromethyl-2-methoxyphenyl,2-hydroxy-4-methylphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl,2-hydroxy-6-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-difluoromethoxyphenyl,3-methoxy-4-(2-chlorothiazol-5-ylmethoxy)phenyl, or5-(hydroxyboryl)-2-methoxyphenyl; (iv) 3,5-difluoro-4-hydroxyphenyl,2,4-dichloro-6-hydroxyphenyl, 2,3-dimethyl-4-methoxyphenyl,4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-2,6-dimethylphenyl,4-hydroxy-3,5-dimethylphenyl, 2,4,6-trihydroxyphenyl,3-hydroxy-4,5-dimethoxyphenyl, or4-hydroxy-5-methoxy-3-dimethylaminophenyl; (v)5-(4-chlorophenyl)furan-2-yl, 5-(hydroxymethyl)furan-2-yl, pyrrol-2-yl,pyrrol-3-yl, 1-phenylsulfonylpyrrol-2-yl, thien-2-yl,2-(pyridin-2-yl)thien-5-yl, 3-(4-fluorophenyl)pyrazol-4-yl,3-chloro-5-trifluoromethylpyrazol-4-yl,1-methyl-3-phenylthiomethyl-5-chloropyrazol-4-yl,1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl,3-(4-fluorophenyl)pyrazol-4-yl, imidazol-4-yl,2-ethyl-5-methylimidazol-4-yl, 2-phenyl-5-chloroimidazol-4-yl,5-methylisoxazol-5-yl, 2-chloro-thiazol-5-yl, 2-aminothiazol-5-yl,4-methylthiazol-5-yl, 2-tetrahydropyrrol-1-ylpyridin-3-yl,3-tetrahydropyrrol-1-ylpyridin-5-yl, 2-(morpholin-4-yl)pyridin-5-yl,2-chloropyridin-3-yl, 2-chloropyridin-5-yl, 2-chloropyridin-6-yl,3-fluoropyridin-2-yl, 2-methoxypyridin-5-yl, pyrazin-2-yl,3,5-dichloropyrazin-2-yl, benzo[d][1,2,3]thiadiazol-5-yl,2-methylindol-3-yl, 1-methyl-2-chloroindol-3-yl,4,5,6,7-tetrafluoroindol-3-yl, 6-fluoro-4H-benzo[d][1,3]dioxin-8-yl, orbenzimidazol-2-yl; or (vi) 1-(benzyloxycarbonyl)tetrahydropyrrol-2-yl,piperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or4-acetylpiperazin-1-yl.
 35. The method of claim 1, wherein R³ ishydrogen.
 36. The method of claim 1, wherein R¹ is hydrogen.
 37. Themethod of a claim 1, wherein R⁴ is CN.
 38. The method of claim 1,wherein R⁴ is aminocarbonyl.
 39. The method of claim 1, wherein R⁴ is—C(O)N═CR^(4a)R^(4b).
 40. The method of claim 39, wherein R^(4b) ishydrogen.
 41. The method of claim 39, wherein R^(4a) is C₆₋₁₄ aryl,optionally substituted with one or more substitutents Q.
 42. The methodof claim 41, wherein R^(4a) is phenyl, optionally substituted with oneor more substitutents Q.
 43. The method of claim 41, wherein R^(4a) ismethoxyphenyl.
 44. The method of claim 1, wherein the salt is an aceticacid salt.
 45. The method of claim 1, wherein the salt is a formic acidsalt.
 46. The method of claim 1, wherein the salt is a camphorsulfonicacid salt.
 47. The method of claim 1, wherein the salt is a hydrobromicacid salt.
 48. The method of claim 1, wherein the salt is a hydrochloricacid salt.
 49. The method of claim 1, wherein the salt is amethanesulfonic acid salt.
 50. The method of claim 1, wherein the saltis a phosphoric acid salt.
 51. The method of claim 1, wherein the saltis a sulfuric acid salt.
 52. The method of claim 1, wherein the salt isa tartaric acid salt.
 53. The method of claim 1, wherein the salt is ap-toluenesulfonic acid salt.
 54. The method of claim 1, wherein the saltis a trifluoroacetic acid salt.
 55. The method of claim 1, wherein thesalt is selected from the group consisting of:3-((3-chlorophenyl)amino)-5-((4-hydroxybenzyl)amino)-3h-pyrazole-4-carboxamidehydrochloride;5-((4-hydroxybenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-3h-pyrazole-4-carboxamidehydrochloride;5-((4-hydroxybenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-3h-pyrazole-4-carboxamidehydrochloride;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamidehydrobromide;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamidehydrochloride;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,acetic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,formic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,camphorsulfonic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,phosphoric acid salt;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,sulfuric acid salt;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,trifluoroacetic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-morpholinophenyl)amino)-3h-pyrazole-4-carboxamide,tartaric acid salt;5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3h-pyrazole-4-carboxamidehydrochloride;5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3h-pyrazole-4-carboxamide,methanesulfonic acid salt;5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3h-pyrazole-4-carboxamide,phosphoric acid salt;5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3h-pyrazole-4-carboxamide,sulfuric acid salt;5-((4-hydroxybenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-3h-pyrazole-4-carboxamide,trifluoroacetic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,camphorsulfonic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,phosphoric acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,sulfuric acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,tartaric acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,p-toluenesulfonic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,trifluoroacetic acid salt;5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3h-pyrazole-4-carboxamidehydrochloride;5-((4-hydroxybenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3h-pyrazole-4-carboxamide,phosphoric acid salt;3-((4-(1h-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3h-pyrazole-4-carboxamidehydrochloride;3-((4-(1h-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3h-pyrazole-4-carboxamide,acetic acid salt;3-((4-(1h-imidazol-1-yl)phenyl)amino)-5-((4-hydroxybenzyl)amino)-3h-pyrazole-4-carboxamide,phosphoric acid salt and3-((1h-indazol-5-yl)amino)-5-((4-hydroxybenzyl)amino)-3h-pyrazole-4-carboxamidehydrochloride; and stereoisomers, enantiomers, mixtures of enantiomers,mixtures of diastereomers, and isotopic variants thereof; andpharmaceutically acceptable solvates, hydrates, and prodrugs thereof.56. A method for the treatment, prevention, or amelioration of one ormore symptoms of an eosinophil-related disorder, disease, or conditionin a subject, which comprises administering to the subject acetic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid,hydrobromic acid, hydrochloric acid, methanesulfonic acid, oxalic acid,phosphoric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,or trifluoroacetic acid salt of a compound of Formula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: R¹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁴ is cyano, aminocarbonyl,—C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b); wherein: R^(4a) is C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; and R^(4b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))R^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; and R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);and each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a) oxo,cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl,each of which is further optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(e), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyl-C₁₋₆ alkyl, each optionally substituted with one or moresubstituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —SF₅,—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 57. A method for the treatment, prevention,or amelioration of one or more symptoms of a basophil-related disorder,disease, or condition in a subject, which comprises administering to thesubject acetic acid, camphorsulfonic acid, citric acid, ethanesulfonicacid, formic acid, hydrobromic acid, hydrochloric acid, methanesulfonicacid, oxalic acid, phosphoric acid, sulfuric acid, tartaric acid,p-toluenesulfonic acid, or trifluoroacetic acid salt of a compound ofFormula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: R¹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁴ is cyano, aminocarbonyl,—C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b); wherein: R^(4a) is C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; and R^(4b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))R^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; and R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);and each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a) oxo,cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl,each of which is further optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyl-C₁₋₆ alkyl, each optionally substituted with one or moresubstituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —SF₅,—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 58. A method for the treatment, prevention,or amelioration of one or more symptoms of a mast cell-related disorder,disease, or condition in a subject, which comprises administering to thesubject acetic acid, camphorsulfonic acid, citric acid, ethanesulfonicacid, formic acid, hydrobromic acid, hydrochloric acid, methanesulfonicacid, oxalic acid, phosphoric acid, sulfuric acid, tartaric acid,p-toluenesulfonic acid, or trifluoroacetic acid salt of a compound ofFormula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: R¹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁴ is cyano, aminocarbonyl,—C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b); wherein: R^(4a) is C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; and R^(4b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; and R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);and each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a) oxo,cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl,each of which is further optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyl-C₁₋₆ alkyl, each optionally substituted with one or moresubstituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —SF₅,—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 59. A method for the treatment, prevention,or amelioration of one or more symptoms of an inflammatory disease in asubject, which comprises administering to the subject acetic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid,hydrobromic acid, hydrochloric acid, methanesulfonic acid, oxalic acid,phosphoric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,or trifluoroacetic acid salt of a compound of Formula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: R¹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁴ is cyano, aminocarbonyl,—C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b); wherein: R^(4a) is C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; and R^(4b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; and R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);and each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a) oxo,cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl,each of which is further optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyl-C₁₋₆ alkyl, each optionally substituted with one or moresubstituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —SF₅,—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 60. The method of claim 1, wherein thedisorder, disease, or condition is selected from the group consisting ofasthma, allergic asthma, exercise induced asthma, allergic rhinitis,perennial allergic rhinitis, seasonal allergic rhinitis, atopicdermatitis, contact hypersensitivity, contact dermatitis,conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, foodallergies, eosinophilic gastroenteritis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, mastocytosis, hyper IgE syndrome,systemic lupus erythematous, psoriasis, acne, multiple sclerosis,allograft rejection, reperfusion injury, chronic obstructive pulmonarydisease, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronicurticaria, basophilic leukocytosis, eczema, arthritis, rheumatoidarthritis, psoriatic arthritis, fibrosis, osteoarthritis, andcardiovascular disorders.
 61. The method of claim 1, wherein thedisorder, disease, or condition is asthma, exercise induced asthma,allergic rhinitis, atopic dermatitis, chronic obstructive plumonarydisease, allergic conjunctivitis, or fibrosis.
 62. The method of claim1, wherein the disorder, disease, or condition is fibrosis.
 63. Themethod of claim 1, wherein the salt is administered in combination witha second therapeutic agent.
 64. A method for modulating RC kinaseactivity, comprising contacting a RC kinase with acetic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid,hydrobromic acid, hydrochloric acid, methanesulfonic acid, oxalic acid,phosphoric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,or trifluoroacetic acid salt of a compound of Formula IA:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable solvate, hydrate, or prodrug thereof; wherein: R¹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² is C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R³ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c), R⁴ is cyano, aminocarbonyl,—C(O)N═CR^(4a)R^(4b), or —C(O)NR^(4a)R^(4b); wherein: R^(4a) is C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; and R^(4b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c), R⁵ is —N(R^(5e))CR^(5a)R^(5c)R^(5d); wherein:R^(5a) is C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;R^(5c) and R^(5d) are each independently hydrogen, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl; and R^(5e) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);and each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together with the Cand N atoms to which they are attached form heterocyclyl; or R^(1b) andR^(1c) together with the N atom to which they are attached formheterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a) oxo,cyano, halo, nitro, and pentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclyl-C₁₋₆ alkyl,each of which is further optionally substituted with one or moresubstituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(1a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(e), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyl-C₁₋₆ alkyl, each optionally substituted with one or moresubstituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) oxo, cyano, halo, nitro, andpentafluorosulfanyl; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclyl-C₁₋₆ alkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —SF₅,—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyl-C₁₋₆ alkyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.